Braf inhibitors and use thereof for treatment of cutaneous reactions

ABSTRACT

The present invention discloses novel BRaf inhibitors, compositions comprising these BRaf inhibitors and uses thereof for the treatment, amelioration and/or prevention of cutaneous reactions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/100,181, filed Nov. 20, 2020, which is a continuation of U.S. patentapplication Ser. No. 16/440,601, filed Jun. 13, 2019, now U.S. Pat. No.10,927,112, which is a continuation of PCT application No.PCT/IL2018/050836, filed Jul. 26, 2018, which claims priority to andbenefit of U.S. Provisional Patent Application Ser. No. 62/538,675,filed on Jul. 29, 2017, the entire contents of each of which are herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to inhibitors of serine/threonine-proteinkinase B-Raf (hereinafter “B-Raf” or “BRaf”) and compositions and usesthereof.

BACKGROUND

Abnormal activation of Epidermal Growth Factor Receptor (EGFR) isinvolved in various diseases, in particular, in several types of cancerssuch as lung cancer, colorectal cancer, head and neck cancer andpancreatic cancer. EGFR antagonists such as monoclonal antibodies (e.g.,cetuximab, panitumumab) and small molecule tyrosine kinase inhibitors(e.g. gefitinib, erlotinib, lapatinib) are used for treating manyEGFR-mediated cancers. While these EGFR antagonists are useful fortreating cancer, they are also associated with severe side effects. Onesuch adverse effect of EGFR antagonists is cutaneous reactions.Cutaneous adverse reactions to EGFR inhibitors include acneiform(papulopustular) rash, abnormal scalp, facial hair and/or eyelashgrowth, paronychia with or without pyogenic granulomas andtelangiectasia.

Various kinases such as phosphatidylinositol-3-kinases (PI 3-kinases),mitogen-activated protein kinases (MAPK), and kinases upstream of MAPKsuch as MEK and MKK, act as downstream effectors of EGFR and many otherreceptor tyrosine kinases and are involved in cellular functions such ascell growth, proliferation, differentiation, motility, survival, andintracellular trafficking. Therapeutic agents that target these pathwaysare also used in the treatment of a number of proliferative diseases,such as melanoma, lung cancer, colorectal cancer, brain cancer, multiplemyeloma, pancreatic cancer and neurofibromatosis. Exemplary therapeuticagents that target these pathways include kinase inhibitors such asTrametinib and Cobimetinib. However, inhibitors of these kinases arealso associated with adverse side effects. For example, cutaneousadverse events caused by MEK inhibitors have been reported, and includeacneiform (papulopustular) rash, abnormal scalp, facial hair and/oreyelash growth, paronychia with or without pyogenic granulomas andtelangiectasia.

BRaf is a protein kinase involved in the regulation of the mitogenactivated protein kinase (MAPK) signaling pathway. Mutations in BRaf caninduce constitutive signaling through the MAPK pathway which may resultin uncontrolled cell proliferation. Use of BRaf inhibitors has beendemonstrated to be associated with inhibition of MAPK signaling, as canbe determined by reduction in levels of phosphorylated ERK, which is thedownstream effector of BRaf. Yet, it has been observed that BRafinhibitors can paradoxically induce an opposite effect of activatingMAPK signaling in BRaf wild-type cells (as determined by increasedlevels of phosphorylated ERK). The underlying mechanisms of paradoxicalMAPK activation have been attributed to dimerization of wild-type BRafand c-Raf and transactivation of the non-inhibited Raf protein leadingto subsequent MAPK pathway activation.

Notwithstanding the underlying mechanism(s) causing the cutaneousadverse reactions, these adverse reactions are a serious drawback of thetreatment with EGFR, PI3K and/or MEK inhibitors, and may lead totreatment discontinuation and/or poor patient compliance.

Carnahan J. et al. (Mol. Cancer Ther. 9(8) August 2010) found thatselective and potent Raf inhibitors can paradoxically stimulate normalcell proliferation. A series of orally bioavailable kinase inhibitorsdisclosed by Smith A. L. et al., J. Med. Chem. 2009, 52, 6189-6192showed potent biochemical activity. For example, Compound 1 of theseries (C-1) showed significant potency (w^(T)B-Raf Ki=1 nmol/L,V600EB-Raf Ki=1 nmol/L, and C-Raf Ki=0.3 nmol/L).

Carnahan et el. found that in cells with wild-type B-Raf and mutatedK-ras, exposure to Raf inhibitors resulted in a dose-dependent andsustained paradoxical activation of mitogen-activated protein kinase(MAPK) signaling. Raf inhibition led to entry into the cell cycle andenhanced proliferation.

N. Shelach showed in a co-pending patent application PCT/IL2017/050301titled “Use of BRaf Inhibitors for Treating Cutaneous Reactions” thatthis paradoxical activation of MAPK can be used for treating cutaneousadverse reactions induced by treatment with EGFR or PI3K inhibitors.

There is still a need in the art for the development of noveltherapeutic compounds, compositions, and methods of treatment, to helpalleviate the aforementioned cutaneous adverse reactions associated withadministration of EGFR inhibitors, PI3K inhibitors, MEK inhibitors orcombinations thereof.

SUMMARY OF THE INVENTION

The present disclosure provides BRaf inhibitors of formula (I), (II),and (III) as defined herein. The present disclosure also providescompositions comprising the compounds of formula (I), (II), and (III)and methods of treating dermatological adverse reactions induced bychemotherapy agents such as EGFR inhibitors, PI3K inhibitors, MEKinhibitors or combinations thereof using the compounds and compositionsof the present disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1D depict ERK Phosphorylation induced in HEKa cells by thecompounds—LUT014, LUT015, and LUT017. FIG. 1A shows Phospho-ERK (upperpanel) and total ERK (lower panel) upon treatment with 0.3 μM of thetest compounds. FIG. 1B shows the densitometric analysis of blots inFIG. 1A based on the calculation of Phospho-ERK/total ERK ratio. FIG. 1Cshows Phospho-ERK (upper panel) and total ERK (lower panel) upontreatment with 1 μM of the test compounds. FIG. 1D shows thedensitometric analysis of blots in FIG. 1C based on the calculation ofPhospho-ERK/total ERK ratio.

FIGS. 2A-2D depict ERK Phosphorylation induced in HEKa by thecompounds—LUT012, LUT016, and C-1. FIG. 2A shows Phospho-ERK (upperpanel) and total ERK (lower panel) upon treatment with 0.3 μM of thetest compounds. FIG. 2B shows the densitometric analysis of blots inFIG. 2A based on the calculation of Phospho-ERK/total ERK ratio. FIG. 2Cshows Phospho-ERK (upper panel) and total ERK (lower panel) upontreatment with 1 μM of the test compounds. FIG. 2D shows thedensitometric analysis of blots in FIG. 2C based on the calculation ofPhospho-ERK/total ERK ratio.

FIGS. 3A-3D depict ERK Phosphorylation induced in HEKa by thecompounds—LUT012, LUT013, LUT014, LUT015, LUT016, LUT017, LUT020 andC-1. FIG. 3A shows Phospho-ERK (upper panel) and total ERK (lower panel)upon treatment with 0.3 μM of the test compounds. FIG. 3B showsPhospho-ERK (upper panel) and total ERK (lower panel) upon treatmentwith 1 μM of the test compounds. FIG. 3C shows the densitometricanalysis of the blot in FIG. 3A based on the calculation ofPhospho-ERK/total ERK ratio. FIG. 3D shows the densitometric analysis ofthe blot in FIG. 3B based on the calculation of Phospho-ERK/total ERKratio.

FIGS. 4A and 4B depict ERK Phosphorylation induced in HEKa by thecompounds—LUT014, LUT017, and C-1. FIG. 4A shows Phospho-ERK (upperpanel) and total ERK (lower panel) upon treatment with 0.003 μM, 0.03μM, and 0.3 μM of the test compounds. FIG. 4B shows the densitometricanalysis of blots in FIG. 4A based on the calculation ofPhospho-ERK/total ERK ratio.

FIGS. 5A-5J depict the effects of the compounds—C-1 (FIG. 5A), LUT-012(FIG. 5B), LUT-014 (FIG. 5C), Vemurafenib (FIG. 5D), LUT-013 (FIG. 5E),LUT-015 (FIG. 5F), LUT-016 (FIG. 5G), LUT-019 (FIG. 5H), LUT-017 (FIG.5I), and LUT-020 (FIG. 5J)—on proliferation of MIA PaCa cells.

FIG. 6 depicts the flow diagram of the Improved Scaled-Up SyntheticProcess for the Preparation of LUT014 (C17071479-F).

FIGS. 7A-7C depict the effect of LU014 on phospho-ERK followingadministration of EGFR (in vitro results). FIG. 7A shows Phospho-ERK andFIG. 7B shows total ERK upon treatment with the test compounds. FIG. 7Cshows the densitometric analysis of blots in FIGS. 7A and 7B based onthe calculation of Phospho-ERK/total ERK ratio.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein are the compounds of formula (I), (II), and (III) andcompositions comprising them. Also provided are methods of treatingcutaneous adverse reactions using the compounds and compositions of thepresent disclosure.

Compounds

In one embodiment, provided herein is a compound of formula (I):

wherein R is selected from the group consisting of 3-ethynylphenyl,3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl,4-chloro-3-(trifluoromethyl)phenyl,3-(1,1-dimethylethyl)-1-methyl-1H-pyrazol-5-yl,3-(trifluoromethoxy)phenyl, 3,5-dihydroxyphenyl or phenyl-3-sulfonamide,or a pharmaceutically acceptable salt or a solvate thereof.

In another embodiment, provided herein is a compound of formula (II):

wherein R is NHR¹, wherein R¹ is 2-fluoro-4-iodophenyl, or apharmaceutically acceptable salt or a solvate thereof.

In another embodiment, provided herein is a compound of formula (III):

wherein R is NHR¹, wherein R¹ is 3-ethynylphenyl,3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl, or4-chloro-3-(trifluoromethyl) phenyl, or a pharmaceutically acceptablesalt or a solvate thereof.

In one embodiment, the compounds of present disclosure inhibit theactivity of BRaf. In one embodiment, the compounds of present disclosuremay have an IC50 towards BRaf of about 0.5×10⁻⁸ M to about 5×10⁻⁸ M,about 1×10⁻⁸ M to about 5×10⁻⁸ M, about 1×10⁻⁸ M to about 3.5×10⁻⁸ M, orabout 1×10⁻⁸ M to about 3×10⁻⁸ M.

In one embodiment, the compounds of present disclosure increase theactivity of Mitogen-Activated Protein Kinases (MAPK).

In one embodiment, the compounds of present disclosure increase theactivity of MAPK and simultaneously inhibit the activity of BRaf.

In one embodiment, the activity of MAPK is determined by measuring thephosphorylation of Extracellular Signal-Regulated Kinase (ERK) andcalculating a ratio of phospho-ERK to total ERK.

In one embodiment, the compounds of the present disclosure increase theratio of phospho-ERK to total ERK by at least about 1.025 fold, 1.05fold, 1.10-fold, 1.15-fold, 1.20-fold, 1.25-fold, 1.30 fold, 1.35-fold,1.40-fold, 1.45-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 2-fold,2.25-fold, 2.5-fold, 2.75-fold, 3-fold, 3.25-fold, 3.5-fold, 3.75-fold,4-fold, 4.25-fold, 4.5-fold, 4.75-fold, 5-fold, 5.25-fold, 5.50-fold,5.75-fold, 6-fold, 6.25-fold, 6.50-fold, 6.75-fold, 7-fold, 7.25-fold,7.5-fold, 8-fold, 8.5-fold, 9-fold, 9.5-fold, 10-fold, 15-fold, 20-fold,25-fold, 30-fold, 40-fold, 50-fold, 75-fold, 100-fold, 150-fold, or byabout 200-fold, including values and ranges therebetween, compared tountreated or control-treated cells.

In one embodiment, the compounds of the present disclosure increase theratio of phospho-ERK to total ERK by about 1.5-fold to about 50-fold,about 1.5-fold to about 25-fold, 1.5-fold to about 20-fold, about1.5-fold to about 15-fold, about 2.5-fold to about 15-fold, about2.5-fold to about 10-fold, about 3-fold to about 20-fold, about 3-foldto about 15-fold, about 4-fold to about 20-fold, about 4-fold to about15-fold, about 4-fold to about 10-fold, about 5-fold to about 20-fold,about 5-fold to about 15-fold, including values and ranges therebetween,compared to untreated or control-treated cells.

In one embodiment, the compounds of the present disclosure increase thelevel of phospho-ERK relative to total ERK by at least about 2.5%, 5%,10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%,80%, 85%, 90%, 95%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%,300%, 325%, 350%, 375% 400%, 425%, 450%, 475%, 500%, 550%, 600%, 650%,700%, 750%, 800%, 850%, 900%, 950%, 1000%, 1100%, 1200%, 1300%, 1400%,1500%, 1600%, 1700%, 1800%, 1900%, 2000%, 2250%, 2500%, 2750%, 3000%,3250%, 3500%, 4000%, 4500%, 4750%, 5000%, 5500%, 6,000%, 6500%, 7,000%,7500%, 8,000%, 9,000%, or 10,000%, including values and rangestherebetween, compared to untreated or control-treated cells.

In one embodiment, the compounds of present disclosure show nophototoxicity or reduced phototoxicity. The level of phototoxicity canbe determined by measuring a Photo-Irritation Factor (PIF) or a MeanPhoto Effect (MPE).

In one embodiment, a PIF can be calculated using the following formula:PIF=IC50(−Irr)/IC50(+Irr), where PIF>5 indicates phototoxicity; 2<PIF<5indicates probable phototoxicity; PIF<2 indicates no phototoxicity. Inone embodiment, the compounds of present disclosure have a PIF of lessthan 5. In another embodiment, the compounds of present disclosure havea PIF of less than 2.

In one embodiment, the MPE can be calculated by comparing the completeconcentration-response curves. MPE is a weighted average of thedifference in response of equivalent doses normalized by the shift inIC50. MPE>0.15 indicates phototoxicity; 0.1<MPE<0.15 indicates probablephototoxicity; MPE<0.1 indicates no phototoxicity. In one embodiment,the compounds of present disclosure have a MPE of less than 0.15. Inanother embodiment, the compounds of present disclosure have a MPE ofless than 0.1.

Compositions

In one embodiment, provided herein are pharmaceutical compositionscomprising a compound of Formula (I):

wherein R is selected from the group consisting of p-chlorophenyl,3-ethynylphenyl, 3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl,4-chloro-3-(trifluoromethyl)phenyl,3-(1,1-dimethylethyl)-1-methyl-1H-pyrazol-5-yl,3-(trifluoromethoxy)phenyl, 3,5-dihydroxyphenyl, phenyl-3-sulfonamide or3-(trifluoromethyl)phenyl, or a pharmaceutically acceptable salt or asolvate thereof, or a combination thereof; and a pharmaceuticallyacceptable carrier or excipient.

In one embodiment, provided herein are pharmaceutical compositionscomprising a compound of Formula (II) or (III) or a pharmaceuticallyacceptable salt or a solvate thereof, and a pharmaceutically acceptablecarrier or excipient.

In another embodiment, provided herein are pharmaceutical compositionscomprising a compound of Formula (I), (II) or (III) or apharmaceutically acceptable salt or a solvate thereof, or a combinationthereof, and a pharmaceutically acceptable carrier or excipient.

In one embodiment, a pharmaceutical composition may comprise about 1%w/w to about 5% w/w of a compound of Formula (I), (II) or (III) or apharmaceutically acceptable salt or a solvate thereof, or a combinationthereof, based on the total weight of the composition. For example, thepharmaceutical composition may comprise about 1%, 1.1%, 1.2%, 1.3%,1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%,2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%3.8%, 3.9%, 4% 4.1%, 4.2%, 4.3% 4.4% 4.5% 4.6%, 4.7% 4.8%, 4.9%, or 5%w/w, including values and ranges therebetween, of any of the compoundsdisclosed herein. In some embodiments, the pharmaceutical compositionmay comprise about 1% to about 3%, about 1% to about 4%, about 1.5% toabout 5%, about 1.5% to about 4.5%, about 1.5% to 3.5%, about 1.5% toabout 3%, about 2% to about 5%, about 2% to about 4.5%, about 2% toabout 4%, about 2.5% to about 5%, about 2.5% to about 4.5%, about 2.5%to about 4%, about 3% to about 5%, about 3.5% to about 5% w/w, includingvalues and ranges therebetween, of any of the compounds disclosedherein.

In one embodiment, a pharmaceutical composition may comprise about 5%w/w to about 10% w/w of a compound of Formula (I), (II) or (III) or apharmaceutically acceptable salt or a solvate thereof, or a combinationthereof, based on the total weight of the composition. For example, thepharmaceutical composition may comprise about 5%, 5.1%, 5.2%, 5.3%,5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%,6.6%, 6.7%, 6.8%, 6.9%, 7%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7.7%,7.8%, 7.9%, 8%, 8.1%, 8.2%, 8.3%, 8.4%, 8.5%, 8.6%, 8.7%, 8.8%, 8.9%,9%, 9.1%, 9.2%, 9.3%, 9.4%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9%, or 10% w/w,including values and ranges therebetween, of any of the compoundsdisclosed herein. In some embodiments, the pharmaceutical compositionmay comprise about 5% to about 9%, about 5% to about 8.5%, about 5% toabout 8%, about 5% to about 7.5%, about 5% to about 7%, about 6% toabout 10%, about 6% to about 9%, about 6% to about 8.5%, about 6% toabout 8%, about 7% to about 10%, about 7% to about 9.5%, about 7% toabout 8.5%, about 7.5% to about 10%, about 8% to about 10% w/w,including values and ranges therebetween, of any of the compoundsdisclosed herein.

In some other embodiments, the pharmaceutical composition may compriseabout 1% to about 10%, about 1% to about 8%, about 1% to about 7%, about2% to about 8%, about 2% to about 7%, about 2% to about 6%, about 2.5%to about 7.5%, about 2.5% to about 5.5%, about 3% to about 8%, about 3%to about 7%, about 4% to about 8%, about 4% to about 7%, about 4.5% toabout 7.5%, about 4.5% to about 7%, or about 4.5% to about 6.5% w/w,including values and ranges therebetween, of any of the compoundsdisclosed herein.

In one embodiment, the pharmaceutical composition comprising any one ofthe compounds disclosed herein is formulated for systemicadministration. Systemic administration can be via enteral or parenteralroute of administration. In one embodiment, systemic administration isoral administration, and the pharmaceutical composition is formulatedfor oral administration (oral pharmaceutical composition).

In one embodiment, provided herein is an oral pharmaceutical compositioncomprising a compound of Formula (I), (II) or (III) or apharmaceutically acceptable salt or a solvate thereof, or a combinationthereof, and a pharmaceutically acceptable carrier or excipient. Oralpharmaceutical compositions of the present disclosure can be in the formof a solid dosage form or a liquid dosage form and may comprise any ofthe disclosed compound(s) in any of the amounts described herein.

In one embodiment, the pharmaceutical composition comprising any one ofthe compounds disclosed herein is formulated for topical administration.Topical administration comprises local application of the composition tothe skin, nails, eyes, eyelashes, eyelids, and/or hair of the subject.

In one embodiment, provided herein is a topical pharmaceuticalcomposition comprising a compound of Formula (I), (II) or (III) or apharmaceutically acceptable salt or a solvate thereof, or a combinationthereof, and a pharmaceutically acceptable carrier or excipient.Compositions for topical administration (topical compositions) can be inthe form of a gel, a hydrogel, an ointment, a cream, a foam, a spray, alotion, a liquid, or a dermal patch and may comprise any of thedisclosed compound(s) in any of the amounts described herein.

In one embodiment, an oral or a topical pharmaceutical compositioncomprises a compound of formula:

in any of the amounts disclosed herein and a pharmaceutically acceptablecarrier or excipient.

In one embodiment, provided herein is a topical pharmaceuticalcomposition comprising LUT014 in any of the w/w % amounts disclosedherein and a pharmaceutically acceptable carrier or excipient. Thetopical composition comprising LUT014 may be formulated in a dosage formselected from ointment, cream, gel, hydrogel, foam, spray, lotion,liquid and dermal patch.

In one embodiment, provided herein is an oral pharmaceutical compositioncomprising LUT014 in any of the w/w % amounts disclosed herein and apharmaceutically acceptable carrier or excipient. The oralpharmaceutical composition comprising LUT014 can be in the form of asolid dosage form or a liquid dosage form.

Solid dosage forms for oral administration include capsules, tablets,powders, and granules. In such solid dosage forms, the active compoundis admixed with at least one inert excipient (or carrier) such as sodiumcitrate or dicalcium phosphate or (a) fillers or extenders, for example,starches, lactose, sucrose, mannitol, and silicic acid; (b) binders, forexample, carboxymethylcellulose, alginates, gelatin,polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, for example,glycerol; (d) disintegrating agents, for example, agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain complexsilicates, and sodium carbonate; (a) solution retarders, for example,paraffin; (f) absorption accelerators, for example, quaternary ammoniumcompounds; (g) wetting agents, for example, cetyl alcohol and glycerolmonostearate; (h) adsorbents, for example, kaolin and bentonite; and (i)lubricants, for example, talc, calcium stearate, magnesium stearate,solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof.In the case of capsules, and tablets, the dosage forms may also comprisebuffering agents.

An exemplary capsule dosage form may comprise soft or hard-filledgelatin capsules comprising one or more compounds of the presentdisclosure and excipients such as lactose or milk sugar, high molecularweight polyethylene glycols, and the like.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Inaddition to the active compounds, the liquid dosage form may containinert diluents commonly used in the art, such as water or othersolvents, solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethylformamide, oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil, and sesame seed oil, glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, or mixtures of these substances, and the like.

Besides such inert diluents, the liquid dosage forms can also includeadjuvants, such as wetting agents, emulsifying and suspending agents,sweetening, flavoring, and perfuming agents. Suspensions, in addition tothe active compound, may contain suspending agents, as for example,ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitanesters, microcrystalline cellulose, aluminum metahydroxide, bentonite,agar-agar, and tragacanth, or mixtures of these substances, and thelike.

An exemplary liquid dosage form for oral administration may comprise asyrup comprising one or more compounds of the present disclosure andexcipients like glycerol, propylene glycol and sucrose.

Topical compositions useful in the present disclosure may be formulatedas a solution. Such compositions may comprise an emollient preferablycontaining from about 1% to about 50% of an emollient(s). As usedherein, the term “emollient” refers to materials used for the preventionor relief of dryness, as well as for the protection of the skin. Anumber of suitable emollients are known and may be used in the presentdisclosure. For example, Sagarin, Cosmetics, Science and Technology, 2ndEdition, Vol. 1, pp. 32-43 (1972) and the International CosmeticIngredient Dictionary and Handbook, eds. Wenninger and McEwen, pp.1656-61, 1626, and 1654-55 (The Cosmetic, Toiletry, and FragranceAssoc., Washington, D.C., 7th Edition, 1997) (hereinafter “ICIHandbook”) contains numerous examples of suitable materials.

A lotion can be made from such a solution. Lotions typically comprisefrom about 1% to about 20% (e.g., from about 5% to about 10%) of anemollient(s) and from about 50% to about 90% (e.g., from about 60% toabout 80%) of water.

Another type of product that may be formulated from a solution is acream. A cream typically comprises from about 5% to about 50% (e.g.,from about 10% to about 20%) of an emollient(s) and from about 45% toabout 85% (e.g., from about 50% to about 75%) of water.

Yet another type of product that may be formulated from a solution is anointment. An ointment may comprise a simple base of animal or vegetableoils or semi-solid hydrocarbons. An ointment may comprise from about 2%to about 10% of an emollient(s) plus from about 0.1% to about 2% of athickening agent(s). A more complete disclosure of thickening agents orviscosity increasing agents useful herein can be found in Sagarin,Cosmetics, Science and Technology, 2nd Edition, Vol. 1, pp. 72-73 (1972)and the ICI Handbook pp. 1693-1697.

The topical compositions useful in the present disclosure may beformulated as emulsions. If the carrier for a topical composition is anemulsion, from about 1% to about 10% (e.g., from about 2% to about 5%)of the carrier comprises an emulsifier(s). Emulsifiers may be nonionic,anionic or cationic. Suitable emulsifiers are disclosed in, for example,in McCutcheon's Detergents and Emulsifiers, North American Edition, pp.317-324 (1986), and the ICI Handbook, pp. 1673-1686.

Lotions and creams can be formulated as emulsions. Such lotions maycomprise from 0.5% to about 5% of an emulsifier(s). Creams may comprisefrom about 1% to about 20% (e.g., from about 5% to about 10%) of anemollient(s); from about 20% to about 80% (e.g., from 30% to about 70%)of water; and from about 1% to about 10% (e.g., from about 2% to about5%) of an emulsifier(s).

The topical compositions of this disclosure can also be formulated as agel (e.g., an aqueous, alcohol, alcohol/water, or oil gel using asuitable gelling agent(s)). Suitable gelling agents for aqueous gelsinclude, but are not limited to, natural gums, acrylic acid and acrylatepolymers and copolymers, and cellulose derivatives (e.g., hydroxymethylcellulose and hydroxypropyl cellulose). Suitable gelling agents for oilsinclude, but are not limited to, hydrogenated butylene/ethylene/styrenecopolymer and hydrogenated ethylene/propylene/styrene copolymer. Gelcompositions may comprise between about 0.1% and 5%, by weight, of suchgelling agents.

In addition to the above carriers and excipients, other emollients andsurface active agents can be incorporated into the topical compositions,including glycerol trioleate, acetylated sucrose distearate, sorbitantrioleate, polyoxyethylene (1) monostearate, glycerol monooleate,sucrose distearate, polyethylene glycol (50) monostearate,octylphenoxypoly (ethyleneoxy) ethanol, decaglycerin penta-isostearate,sorbitan sesquioleate, hydroxylated lanolin, lanolin, triglyceryldiisostearate, polyoxyethylene (2) oleyl ether, calciumstearoyl-2-lactylate, methyl glucoside sesquistearate, sorbitanmonopalmitate, methoxy polyethylene glycol-22/dodecyl glycol copolymer(Elfacos E200), polyethylene glycol-45/dodecyl glycol copolymer (ElfacosST9), polyethylene glycol 400 distearate, and lanolin derived sterolextracts, glycol stearate and glycerol stearate; alcohols, such as cetylalcohol and lanolin alcohol; myristates, such as isopropyl myristate;cetyl palmitate; cholesterol; stearic acid; propylene glycol; glycerin,sorbitol and the like.

Methods

Provided herein are methods of treating, preventing, and/or amelioratingdermatological conditions.

In one embodiment, the dermatological condition is a dermatological orcutaneous adverse reactions induced by chemotherapy agents such as EGFRinhibitors, PI3K inhibitors, MEK inhibitors or combinations thereof.

In one embodiment, provided herein is a method for treating,ameliorating, and/or preventing a cutaneous adverse reaction of EGFRinhibitors, PI3K inhibitors, MEK inhibitors or combinations thereof in asubject in need thereof, comprising administering a therapeuticallyeffective amount of a composition comprising a compound of formula (I)

wherein R is selected from the group consisting of p-chlorophenyl,3-ethynylphenyl, 3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl,4-chloro-3-(trifluoromethyl)phenyl,3-(1,1-dimethylethyl)-1-methyl-1H-pyrazol-5-yl,3-(trifluoromethoxy)phenyl, 3,5-dihydroxyphenyl, phenyl-3-sulfonamide or3-(trifluoromethyl)phenyl, or a pharmaceutically acceptable salt or asolvate thereof;

a compound of formula (II):

wherein R is NHR¹, wherein R¹ is 2-fluoro-4-iodophenyl, or apharmaceutically acceptable salt or a solvate thereof;

a compound of formula (III):

wherein R is NHR¹, wherein R¹ is 3-ethynylphenyl,3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl, or4-chloro-3-(trifluoromethyl) phenyl, or a pharmaceutically acceptablesalt or a solvate thereof;

or a combination thereof; and a pharmaceutically acceptable carrier orexcipient.

In one embodiment, methods for treating, ameliorating, and/or preventinga cutaneous adverse reaction of EGFR inhibitors, PI3K inhibitors, MEKinhibitors or combinations thereof in a subject in need thereof compriseadministering a therapeutically effective amount of a compositioncomprising a compound of formula (I), wherein R is selected from thegroup consisting of p-chlorophenyl, 3-ethynylphenyl,3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl,4-chloro-3-(trifluoromethyl)phenyl,3-(1,1-dimethylethyl)-1-methyl-TH-pyrazol-5-yl,3-(trifluoromethoxy)phenyl, 3,5-dihydroxyphenyl, phenyl-3-sulfonamide or3-(trifluoromethyl)phenyl, or a pharmaceutically acceptable salt or asolvate thereof, or a combination thereof; and a pharmaceuticallyacceptable carrier or excipient.

In one embodiment, methods for treating, ameliorating, and/or preventinga cutaneous adverse reaction of EGFR inhibitors, PI3K inhibitors, MEKinhibitors or combinations thereof in a subject in need thereof compriseadministering a therapeutically effective amount of a compositioncomprising a compound of formula (II), wherein R is NHR¹, wherein R¹ is2-fluoro-4-iodophenyl, or a pharmaceutically acceptable salt or asolvate thereof; and a pharmaceutically acceptable carrier or excipient.

In one embodiment, methods for treating, ameliorating, and/or preventinga cutaneous adverse reaction of EGFR inhibitors, PI3K inhibitors, MEKinhibitors or combinations thereof in a subject in need thereof compriseadministering a therapeutically effective amount of a compositioncomprising a compound of formula (III), wherein R is NHR¹, wherein R¹ is3-ethynylphenyl, 3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl, or4-chloro-3-(trifluoromethyl) phenyl, or a pharmaceutically acceptablesalt or a solvate thereof, or a combination thereof; and apharmaceutically acceptable carrier or excipient.

In one embodiment, methods for treating, ameliorating, and/or preventinga cutaneous adverse reaction of EGFR inhibitors, PI3K inhibitors, MEKinhibitors or combinations thereof in a subject in need thereof compriseadministering a therapeutically effective amount of a compositioncomprising a combination of any of the compounds disclosed herein and apharmaceutically acceptable carrier or excipient.

In one embodiment, methods for treating, ameliorating, and/or preventinga cutaneous adverse reaction of EGFR inhibitors, PI3K inhibitors, MEKinhibitors or combinations thereof in a subject in need thereof compriseadministering a therapeutically effective amount of a compositioncomprising a compound of formula

in any of the w/w % amounts disclosed herein and a pharmaceuticallyacceptable carrier or excipient.

Dermatological or cutaneous adverse reactions induced by chemotherapyagents such as EGFR inhibitors, PI3K inhibitors, MEK inhibitors orcombinations thereof include acneiform rash, papulopustular rash,abnormal scalp hair growth, abnormal facial hair growth, abnormal hairgrowth, abnormal eyelash growth, xerosis, pruritus, paronychia with orwithout pyogenic granulomas and telangiectasia. The methods describedherein treat, ameliorate, and/or prevent one or more of these adversereactions.

In one embodiment, a cutaneous adverse reaction of EGFR inhibitors, PI3Kinhibitors, MEK inhibitors or combinations thereof that is treated,ameliorated, and/or prevented by the compounds/compositions of thepresent disclosure is acneiform rash.

In one embodiment, the subject is a mammal such as a human, dog, and/orcat.

In one embodiment, the subject is receiving an EGFR inhibitor, PI3Kinhibitor, MEK inhibitor or a combination thereof at the time ofadministering the compounds/compositions of the present disclosure. Inanother embodiment, the compounds/compositions of the present disclosureare administered to the subject prior to or after administration of anEGFR inhibitor, PI3K inhibitor, MEK inhibitor or a combination thereof.

In some embodiments, methods disclosed herein comprise systemic ortopical administration of a therapeutically effective amount of thecompounds/compositions of the present disclosure.

Methods comprising topical administration comprise local administrationor application of any of the compositions disclosed herein to the skin,nails, eyes, eyelashes, eyelids, and/or hair of the subject. In someembodiments, topical administration comprises topically administering acomposition formulated in a dosage form selected from a gel, a hydrogel,an ointment, a cream, a spray, a dermal patch, a foam, a lotion and aliquid.

Systemic administration comprises enteral administration or parenteraladministration. In some embodiments of the methods disclosed herein, thesystemic administration comprises oral administration. In someembodiments of the methods disclosed herein, oral administrationcomprises administration of an oral dosage form selected from tablet,capsule, liquid, suspension and powder.

In one embodiment, methods disclosed herein comprise systemically ortopically administering about 0.1 mg/day to about 1 mg/day of one ormore compounds of the present disclosure. In some embodiments, methodsdisclosed herein comprise systemically or topically administering about0.1 mg/day, about 0.2 mg/day, about 0.3 mg/day, about 0.4 mg/day, about0.5 mg/day, about 0.6 mg/day, about 0.7 mg/day, about 0.8 mg/day, about0.9 mg/day, or about 1 mg/day, including values and ranges therebetween,of one or more compounds of the present disclosure. In some embodiments,methods disclosed herein comprise systemically or topicallyadministering about 0.1 mg/day to about 0.5 mg/day, about 0.2 mg/day toabout 0.8 mg/day, about 0.2 mg/day to about 0.5 mg/day, or about 0.5mg/day to about 1 mg/day, including values and ranges therebetween, ofone or more compounds of the present disclosure.

In one embodiment, methods disclosed herein comprise systemically ortopically administering about 1 mg/day to about 5 mg/day of one or morecompounds of the present disclosure. In some embodiments, methodsdisclosed herein comprise systemically or topically administering about1 mg/day, 1.5 mg/day, 2 mg/day, 2.5 mg/day, 3 mg/day, 3.5 mg/day, 4mg/day, 4.5 mg/day, or 5 mg/day, including values and rangestherebetween, of one or more compounds of the present disclosure.

In one embodiment, methods disclosed herein comprise systemically ortopically administering about 5 mg/day to about 10 mg/day of one or morecompounds of the present disclosure. In some embodiments, methodsdisclosed herein comprise systemically or topically administering about5 mg/day, about 5.5 mg/day, about 6 mg/day, about 6.5 mg/day, about 7mg/day, about 7.5 mg/day, about 8 mg/day, about 8.5 mg/day, about 9mg/day, about 9.5 mg/day, or about 10 mg/day, including values andranges therebetween, of one or more compounds of the present disclosure.

In some embodiments, methods disclosed herein comprise systemically ortopically administering about 1 mg/day to about 10 mg/day, about 1mg/day to about 8 mg/day, about 2 mg/day to about 8 mg/day, about 2.5mg/day to about 7.5 mg/day, about 3 mg/day to about 8 mg/day, about 3mg/day to about 6 mg/day, or about 4 mg/day to about 8 mg/day, includingvalues and ranges therebetween, of one or more compounds of the presentdisclosure.

In one embodiment, the amount of the compound administered depends onthe nature of the compound, the mode of administration, and/or theseverity of the cutaneous reaction. The therapeutically effective amountthat need to be administered to a patient can be determined bydose-ranging clinical studies known in the art.

In some embodiments of the methods disclosed herein, an EGFR inhibitoris selected from Iressa (gefitinib), Tarceva (erlotinib), Tykerb(Lapatinib), Erbitux (cetuximab), Vectibix (panitumumab), Caprelsa(vandetanib), Portrazza (necitumumab), Tagrisso (osimertinib) andcombinations thereof.

In some embodiments of the methods disclosed herein, a PI3K inhibitor isselected from GDC-0980 (Apitolisib), GDC-0941 (Pictilisib), BAY 80-6946(Copanlisib), BKM120 (Puparlisib), NVP-BEZ235 (Dactolisib), IPI 145(Duvelisib), Idelalisib (GS-1101 or CAL-101), wortmannin, LY294002 andcombinations thereof.

In some embodiments of the methods disclosed herein, a MEK inhibitor isselected from Trametinib (GSK1120212), Cobimetinib (XL518), Binimetinib(MEK162), Selumetinib, PD-325901, CI-1040, PD035901, UO126, TAK-733, andcombinations thereof.

In one embodiment, the methods disclosed herein reduce the severity ofthe cutaneous adverse reactions.

The most commonly used system to grade the severity of cutaneous adversereactions is National Cancer Institute's Common Terminology Criteria forAdverse Events (CTCAE) version 4.0, which recognizes 4 grades shown inTable 1 below.

TABLE 1 NCI-CTCAE version 4.0 grading scale of skin and subcutaneoustissue disorders Grade 1 Papules and/or pustules covering <10% of theBSA associated or not associated with symptoms of pruritus or tendernessGrade 2 Papules and/or pustules covering 10-30% of the BSA associated ornot associated with symptoms of pruritus or tenderness; psychosocialimpact; limiting instrumental ADL Grade 3 Papules and/or pustulescovering >30% of the BSA associated or not associated with pruritus ortenderness; limiting self-care ADL, associated with local superinfection(oral antibiotics indicated) Grade 4 Covering any percentage of the BSAassociated or not with pruritus or tenderness; associated with severesuperinfection (intravenous antibiotics indicated); life-threateningconsequences BSA = Body surface area; ADL = activity of daily living

In one embodiment, the methods disclosed herein reduce the severity ofthe cutaneous adverse reactions from grade 4 to grade 3, 2, 1, or 0, asdefined by National Cancer Institute Common Terminology Criteria forAdverse Events (NCI-CTCAE) version 4.0.

In one embodiment, the methods disclosed herein reduce the severity ofthe cutaneous adverse reactions from grade 3 to grade 2, 1, or 0, asdefined by NCI-CTCAE version 4.0.

In one embodiment, the methods disclosed herein reduce the severity ofthe cutaneous adverse reactions from grade 2 to grade 1 or 0, as definedby NCI-CTCAE version 4.0.

In one embodiment, the methods disclosed herein reduce the severity ofthe cutaneous adverse reactions from grade 1 to grade 0, as defined byNCI-CTCAE version 4.0.

In one embodiment, the methods disclosed herein prevent, partially orcompletely, the development of cutaneous adverse reactions.

In one embodiment, the methods disclosed herein prevent, partially orcompletely, the development of grade 4, grade 3, grade 2, or grade 1 ofthe cutaneous adverse reactions, as defined by NCI-CTCAE version 4.0.

In one embodiment, the methods disclosed herein prevent the escalationof the cutaneous adverse reaction. For example, in one embodiment, themethods disclosed herein prevent the escalation of the cutaneous adversereaction from grade 0 to grade 1, 2, 3, or 4, as defined by NCI-CTCAEversion 4.0. In another embodiment, the methods disclosed herein preventthe escalation of the cutaneous adverse reaction from grade 1 to grade2, 3, or 4, as defined by NCI-CTCAE version 4.0. In another embodiment,the methods disclosed herein prevent the escalation of the cutaneousadverse reaction from grade 2 to grade 3 or 4, as defined by NCI-CTCAEversion 4.0. In another embodiment, the methods disclosed herein preventthe escalation of the cutaneous adverse reaction from grade 3 to grade4, as defined by NCI-CTCAE version 4.0.

Another system that may be used to grade the severity of cutaneousadverse reactions is Lacouture grading scale shown in Table 2 below.

TABLE 2 Adverse Event Grade 1 Grade 2 Grade 3 Grade 4 Papulopustular 1APapules or 1B Papules or 2A Papules or 2B Papules or 3A Papules or 3BPapules or eruption pustules <5 pustules <5; pustules 6-20; pustules6-20; pustules >20; pustules >20; Grading OR 1 area of OR 1 area of OR2-5 areas OR 2-5 areas OR more than 5 OR more than 5 individually forerythema or erythema or of erythema or of erythema or areas of areas offace, scalp, chest edema <1 cm edema <1 cm edema <1 cm edema <1 cmerythema or erythema or or back) in size in size AND in size in size ANDedema <1 cm edema <1 cm pain or pain, pruritus, in size in size ANDpruritus or effect on pain, pruritus, emotions or or effect onfunctioning emotions or functioning Nail changes-Nail Onycholysis orridging without Onycholysis with mild/moderate Nail plate changesinterfering with Plate pain pain; any nail plate lesion self-care ADLinterfering with instrumental ADL Nail changes-Nail Disruption orabsence of cuticle; Erythematous/tender/painful; Periungual abscess: ORfold fold OR erythema OR pyogenic granuloma; OR changes interfering withself-care crusted lesions OR any fold ADL lesion interfering oninstrumental ADL Nail changes-Digit Xerosis AND/OR erythema XerosisAND/OR erythema with Digit tip lesions interfering with self- tipwithout pain mild/moderate pain or stinging; care ADL OR fingertipfissures; OR any digit tip lesion interfering with instrumental ADLErythema Painless erythema, blanching; Painful erythema, blanching;Painful erythema, nonblanching; erythema covering <10% BSA erythemacovering 10-30% BSA erythema covering >30% BSA Pruritus Mild ORlocalized, intermittent, 2A Moderate 2B Moderate Severe, widespreadconstant AND not requiring therapy. localized OR localized ORinterfering with sleep widespread widespread intermittent constant ANDAND Requiring Requiring intervention intervention XerosisScaling/flaking covering <10% 2A 2B 3A 3B BSA NO Scaling/flakingScaling/flaking + Scaling/flaking Scaling/flakingerythema/pruritus/effect on covering 10-30% pruritus covering >30%covering >30% emotions or functioning BSA + covering 10-30% BSA AND BSAAND pruritus OR BSA AND pruritus AND pruritus AND effect on effect onerythema AND erythema AND emotions/ emotions/ effect on effect onfunctioning functioning + emotions/ emotions/ erythema functioning ANDfunctioning AND fissuring/ fissuring/ cracking + cracking + fissuring/signs of super cracking infection Hair changes; Terminal hair loss <50%of 2A: Hair loss 2B: Marked Scalp hair loss or normal for thatindividual that associated loss of at least alopecia may or may not benoticeable to with marked 75% hair others but is associated withincrease in compared to increased shedding and overall shedding andnormal for that feeling of less volume. May 50%-74% loss individual withrequire different hair style to compared to inability to cover but doesnot require normal for that camouflage hairpiece to camouflageindividual. except with a Hair loss is full wig OR apparent to newcicatricial others, may hair loss be difficult to documented camouflageby biopsy that with change in covers at least hair style and 5% scalpmay require surface area. hairpiece. May impact on functioning insocial, personal or professional situations. Hair Changes: Somedistortion of hair growth 2A: Distortion 2B: Distortion disruption ofbut does not cause symptoms of hair growth of hair growth normal hairgrowth or require intervention. in many hairs of most hairs (specify):in a given in a given Facial hair area that area with (diffuse, notcause symptoms or just in male discomfort or resultant beard/mustachesymptoms that problems areas) may require requiring Eyelashes individualremoval of Eyebrows hairs to be multiple Body Hair removed. hairs. Beardand moustache hair Hair Changes: Increase in length, thickness 2A:Increase 2B: Marked increased hair and/or density of hair that the inlength, increase in changes (specify): patient is able to camouflage bythickness hair density, Facial hair periodic shaving, bleaching orand/or density thickness (diffuse, not removal of individual hairs. ofhairs that and/or length just in male is very of hair thatbeard/mustache noticeable and requires either areas) requires frequentEyelashes regular shaving or Eyebrows shaving or destruction of BodyHair removal of the hair to Beard and hairs in order camouflage.moustache hair to camouflage. May cause (hirsutism) May cause symptomsmild symptoms related to hair related to hair overgrowth. overgrowth.Without hair removal, inability to function normally in social, personalor professional situations. Flushing 1A. 1B. 2A. 2B. 3A. 2B. Face ORchest, Any location, Symptomatic Symptomatic Face and chest, Face andchest, asymptomatic, asymptomatic, on face, or on face, or transient,permanent, transient permanent chest, transient chest, permanentsymptomatic symptomatic Telangiectasia One area (<1 cm diameter) NOT 2A2B More than 6 affecting emotions or 2-5 (<1 cm 2-5 (<1 cm (<1 cmdiameter) functioning diameter) diameter) OR confluent areas NOT areasareas affecting affecting affecting emotions or emotions or emotions orfunctioning functioning functioning Hyperpigmentation One area (<1 cmdiameter) NOT 2A 2B More than 6 affecting emotions or 2-5 (<1 cm 2-5 (<1cm (<1 cm diameter) functioning diameter) diameter) OR confluent areasNOT areas areas affecting affecting affecting emotions or emotions oremotions or functioning functioning functioning Mucositis Mild erythemaor edema, and Symptomatic (mild pain, opioid Pain requiring opioidanalgesic; erythema and Oral asymptomatic not required); erythema orerythema and ulceration, cannot eat ulceration, Anal limited ulceration,can eat solid solids, can swallow liquids (Oral cannot foods and takeoral medication mucositis only) tolerate PO (Oral mucositis only)intake; require tube feeding or hospitalization (Oral mucositis only)Radiation Faint erythema or dry Moderate to brisk erythema; Moistdesquamation other than skin Skin necrosis dermatitis desquamationpatchy moist desquamation, folds and creases; bleeding induced orulceration mostly confined to skin folds by minor trauma or abrasion offull and creases; moderate edema thickness dermis; spontaneous bleedingfrom involved site Hyposalivation Can eat but requires liquids, noModerate/thickened saliva: No saliva, unable to speak without effect onspeech cannot eat dry foods, mild water, no oral intake without waterspeech impairment (sticky tongue, lips, affecting speech) Taste Alteredor reduced taste; no Altered or reduced taste Taste abnormalities,requires impact on oral intake affecting interest and ability tointervention eat no intervention required

In one embodiment, the methods disclosed herein reduce the severity ofthe cutaneous adverse reactions from grade 4 to grade 3B, 3A, 2B, 2A,1B, or 1A, as defined by Lacouture grading scale.

In one embodiment, the methods disclosed herein reduce the severity ofthe cutaneous adverse reactions from grade 3B to grade 3A, 2B, 2A, 1B,or 1A, as defined by Lacouture grading scale.

In one embodiment, the methods disclosed herein reduce the severity ofthe cutaneous adverse reactions from grade 3A to grade 2B, 2A, 1B, or1A, as defined by Lacouture grading scale.

In one embodiment, the methods disclosed herein reduce the severity ofthe cutaneous adverse reactions from grade 2B to grade 2A, 1B, or 1A, asdefined by Lacouture grading scale.

In one embodiment, the methods disclosed herein reduce the severity ofthe cutaneous adverse reactions from grade 2A to grade 1B or 1A, asdefined by Lacouture grading scale.

In one embodiment, the methods disclosed herein reduce the severity ofthe cutaneous adverse reactions from grade 1B to grade 1A, as defined byLacouture grading scale.

In one embodiment, the methods disclosed herein prevent, partially orcompletely, the development of grade 4, grade 3B, grade 3A, grade 2B,grade 2A, grade 1B, or grade 1A of the cutaneous adverse reactions, asdefined by Lacouture grading scale.

In one embodiment, the methods disclosed herein prevent the escalationof the cutaneous adverse reaction from grade 1A to grade 1B, 2A, 2B, 3A,3B or 4, as defined by Lacouture grading scale. In another embodiment,the methods disclosed herein prevent the escalation of the cutaneousadverse reaction from grade 1B to grade 2A, 2B, 3A, 3B or 4, as definedby Lacouture grading scale. In one embodiment, the methods disclosedherein prevent the escalation of the cutaneous adverse reaction fromgrade 2A to grade 2B, 3A, 3B or 4, as defined by Lacouture gradingscale. In one embodiment, the methods disclosed herein prevent theescalation of the cutaneous adverse reaction from grade 2B to grade 3A,3B or 4, as defined by Lacouture grading scale. In one embodiment, themethods disclosed herein prevent the escalation of the cutaneous adversereaction from grade 3A to grade 3B or 4, as defined by Lacouture gradingscale. In one embodiment, the methods disclosed herein prevent theescalation of the cutaneous adverse reaction from grade 3B to grade 4,as defined by Lacouture grading scale.

EXAMPLES

The following examples illustrate certain embodiments of the inventionbut are not meant to limit the scope of the claims in any way. Thefollowing examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the described invention and are not intended to limit thescope of what the inventors regard as their invention nor are theyintended to represent that the experiments below are all or the onlyexperiments performed. Efforts have been made to ensure accuracy withrespect to numbers used (e.g. amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Centigrade,and pressure is at or near atmospheric.

Exemplary methods for synthesizing the compounds of formula I(LUT012-LUT017 and LUT019-LUT020) are disclosed in Examples 1-9.

The known compound C-1 was prepared according to the synthetic proceduredetailed in Smith A. L. et al., J. Med. Chem. 2009, 52, 6189-6192.

Example 1 Synthesis of Compound of Formula I, R=3-Ethynylphenyl(Compound LUT012) Preparation of Intermediate 3B-2

To a mixture of compound 3B-1 (2.00 g, 8.98 mmol, 1.0 eq) in isopropanol(20 mL) was added compound 3B-3 (1.26 g, 10.8 mmol, 1.2 eq) andtrifluoroacetic acid (1.02 g, 8.98 mmol, 665 uL, 1.0 eq) at 20° C. undernitrogen. The resulting mixture was heated to 90° C. and stirred at 90°C. for 16 h. TLC (petroleum ether:ethyl acetate=3:1, R_(f-SM)=0.43,R_(f-DP)=0.24) showed the reaction was completed. The reaction mixturewas filtered and filter cake was washed with dichloromethane (10 mL),the filter cake was collected and dried in vacuum to give compound 3B-2(2.60 g, 8.57 mmol, 95.4% yield) as a yellow solid, which was used fornext step without further purification.

¹H NMR: ET15201-1-PTA 400 MHz MeOD

δ 8.74 (d, J=8.8 Hz, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.71 (s, 1H),7.60-7.71 (m, 4H), 7.10 (d, J=7.2 Hz, 1H), 3.73 (s, 1H), 2.61 (s, 3H).

Preparation of Intermediate 3B

To a mixture of compound 3B-2 (2.60 g, 8.57 mmol, 1.0 eq) in ethanol (26mL) was added SnCl₂.2H₂O (9.67 g, 42.9 mmol, 5.0 eq) at 20° C. undernitrogen. The resulting mixture was heated to 85° C. and stirred at 85°C. for 16 h. TLC (petroleum ether:ethyl acetate=2:1, R_(f-SM)=0.43,R_(f-DP)=0.30) showed the reaction was completed. The reaction mixturewas cooled to 20° C. and poured into 5 N NaOH aqueous (50 mL) andstirred for 5 min, filtered and the aqueous phase was extracted withdichloromethane (50 mL, 20 mL). The combined organic phase was driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuum to givecompound 3B (2.30 g, crude) as a brown solid, which was used for nextstep without further purification.

1H NMR: ET15201-4-PTA 400 MHz DMSO-d₆

δ 8.96 (s, 1H), 8.12 (s, 1H), 7.90-7.93 (m, 2H), 7.64 (d, J=8.0 Hz, 1H),7.45 (d, J=6.0 Hz, 1H), 7.25-7.31 (m, 2H), 7.04 (d, J=6.0 Hz, 1H), 5.51(s, 2H), 4.13 (s, 1H), 2.26 (s, 3H).

Preparation of Intermediate 4B

To a mixture of compound 3 (1.00 g, 3.34 mmol, 1.0 eq) and compound 3B(913 mg, 3.34 mmol, 1.0 eq) in tetrahydrofuran (10 mL) was added LiHMDS(1 M, 16.7 mL, 5.0 eq) at 0° C. under nitrogen. The resulting mixturewas stirred at 0° C. for 1 h. TLC (petroleum ether:ethyl acetate=2:1,R_(f-SM)=0.25, R_(f-DP)=0.40) showed the reaction was completed. Thereaction mixture was quenched with drop-wise addition of ice-water (2mL) at 0° C. resulting in a light orange solution containing a whitesolid in suspension. The mixture was concentrated to give a yellow solidwhich was suspended in ethyl acetate (50 mL), dried with Na₂SO₄,filtered through a plug of Celite to give a yellow solution and wasconcentrated in vacuum. The residue was washed with methyl tert-butylether (20 mL), filtered to afford the filter cake and the filter cakewas dried in vacuum to afford compound 4B (1.10 g, 1.99 mmol, 59.6%yield) as light-yellow solid.

¹H NMR: ET15201-9-P1A 400 MHz DMSO-d₆

δ 11.69 (s, 1H), 9.66 (dd, J=6.0, 1.6 Hz, 1H), 9.28 (s, 1H), 9.12 (s,1H), 8.97 (s, 1H), 8.42 (d, J=8.8 Hz, 1H), 8.13 (s, 1H), 8.06 (dd,J=2.8, 1.6 Hz, 1H), 7.93-7.96 (m, 2H), 7.60 (d, J=8.8 Hz, 2H), 7.33 (t,J=8.0 Hz, 1H), 7.16 (d, J=6.0 Hz, 1H), 7.08 (d, J=7.6 Hz, 1H), 6.91 (q,J=3.2 Hz, J=0.8 Hz, 1H), 5.89 (d, J=8.8 Hz, 1H), 4.02-4.14 (m, 1H),3.74-3.79 (m, 1H), 2.36 (s, 4H), 1.99-2.08 (m, 2H), 1.10 (s, 1H).

Preparation of Compound of Formula I, R=3-Ethynylphenyl (CompoundLUT012)

Compound 4B (1.10 g, 1.99 mmol, 1.0 eq) was suspended in HCl (0.5 M,35.8 mL, 9.0 eq) at 20° C. under nitrogen. The mixture was heated to100° C. and stirred for 1 hour. LCMS (ET15201-11-P1A1) showed thereaction was completed. The hot solution was filtered, washing withboiling water (2×20 mL). The resulting solution was cooled in an icebath and product was crystallized from solution as a yellow solid. Thesolid was filtered and added to saturated aq. Na₂CO₃ (100 mL). Themixture was stirred for 10 min and then was filtered, the filtered cakewas washed with water (50 mL) and collected as crude product. The crudeproduct was purified by prep-TLC (petroleum ether/ethyl acetate=1/1,R_(f)=0.4) to afford LUT012 (110 mg, 230 umol, 11.6% yield, 98.1%purity) as a yellow solid.

¹HNMR: ET15201-11-P1A2 400 MHz DMSO-d₆

δ 13.84 (br. s, 1H), 11.84 (s, 1H), 9.76 (d, J=7.2 Hz, 1H), 9.25 (s,1H), 9.06 (s, 1H), 8.73 (s, 1H), 8.41 (d, J=8.4 Hz, 1H), 8.12 (s, 1H),8.05 (d, J=4.8 Hz, 1H), 7.94 (d, J=6.4 Hz, 2H), 7.61 (d, J=8.4 Hz, 1H),7.31 (q, J=7.6 Hz, 1H), 7.16 (d, J=5.6 Hz, 1H), 7.08 (d, J=7.6 Hz, 1H),6.92 (q, J=4.8 Hz, J=3.2 Hz, 1H), 4.14 (s, 1H), 2.37 (s, 3H).

Example 2 Synthesis of Compound of Formula I,R=1,1-dimethylethyl)-1-methyl-1H-pyrazol-5-yl (LUT013) Preparation ofIntermediate 3C-2

Compound 3B-1 (1.00 g, 4.49 mmol, 1.0 eq),5-tert-butyl-2-methyl-pyrazol-3-amine (1.38 g, 8.98 mmol, 2.0 eq),Pd₂(dba)₃ (82.3 mg, 89.8 umol, 0.02 eq), DavePhos (70.7 mg, 180 umol,0.04 eq) and LiHMDS (1 M, 9.10 mL, 2.0 eq) were taken up into amicrowave tube in dioxane (10 mL). The sealed tube was heated at 150° C.for 30 min under microwave. TLC (petroleum ether:ethyl acetate=1:1,R_(f)=0.71), LCMS (ET15300-11-P1A, product RT=0.972), LCMS(ET15300-11-P1B, product RT=0.973) showed the starting material wasconsumed completely. The two reaction mixture were combined andconcentrated in reduced pressure at 40° C. The residue was purified bysilica gel chromatography (100-200 mesh silica gel), eluted withpetroleum ether:ethyl acetate (80:1-0:1) to afford compound 3C-2 (1.00g, 2.95 mmol, 32.8% yield) as yellow solid.

¹H NMR: ET15300-11-P1A 400 MHz CDCl₃

δ 8.16 (d, J=6.0 Hz, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.45 (d, J=8.8 Hz,1H), 7.01 (d, J=6.0 Hz, 1H), 6.08 (s, 1H), 3.72 (s, 3H), 2.55 (s, 3H),1.34 (s, 9H).

Preparation of Intermediate 3C

A mixture of compound 3C-2 (1.00 g, 2.95 mmol, 1.0 eq) in ethyl alcohol(20 mL) was added SnCl₂.2H₂O (3.32 g, 14.7 mmol, 5.0 eq) in one portionat 20° C. under nitrogen. And then the reaction mixture was heated to80° C. for 12 hrs. TLC (petroleum ether:ethyl acetate=0:1, R_(f)=0.24)and LCMS (ET15300-12-P1A, product: RT=0.793) showed the reaction wascompleted. The mixture was cooled to 40° C. and concentrated in reducedpressure at 40° C. The residue was poured into dichloromethane (20 mL).The combined organic phase was washed with 5 N aqueous NaOH (10 mL) andstirred for 5 min, the mixture was filtered and concentrated in vacuum.The aqueous phase was extracted with dichloromethane (20 mL, 10 mL). Thecombined organic phase was washed with brine (15 mL), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by silica gel chromatography (100-200 mesh silica gel), elutedwith petroleum ether:ethyl acetate (50:1˜0:1) to afford crude compound3C (700 mg, 2.26 mmol, 76.8% yield) as yellow solid.

¹H NMR: ET15300-12-P1A 400 MHz CDCl₃

δ 7.95 (d, J=6.0 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.13 (d, J=8.8 Hz,1H), 6.97 (d, J=6.0 Hz, 1H), 6.58 (s, 1H), 4.08 (s, 2H), 3.65 (s, 3H),2.29 (s, 3H), 1.27 (s, 9H).

Preparation of Intermediate 4C

To a solution of compound 3C (310 mg, 1.00 mmol, 1.0 eq) and compound 3(300 mg, 1.00 mmol, 1.0 eq) in tetrahydrofuran (4.0 mL) was addedLi-HMDS (1 M, 5.0 mL, 5.0 eq) drop-wise at 0° C. over a period of 60mins under nitrogen. TLC (petroleum ether:ethyl acetate=0:1, R_(f)=0.34)and LCMS (ET15300-15-P1A, product RT=0.922) showed the reaction wascompleted. The mixture was concentrated in reduced pressure at 40° C. toafford crude compound 4C (1.00 g, crude) as yellow solid.

Note: Avoid contact with water.

¹H NMR: ET15300-15-P1A 400 MHz MeOD

δ 9.72 (dd, J=1.6 Hz, J=7.6 Hz, 1H), 9.04 (s, 1H), 8.71 (s, 1H), 8.20(d, J=8.4 Hz, 1H), 7.98-8.00 (m, 1H), 7.70 (d, J=6.4 Hz, 1H), 7.59 (d,J=8.8 Hz, 1H), 7.19 (d, J=6.0 Hz, 1H), 6.90 (q, J=5.2 Hz, 1H), 6.07 (s,1H), 5.92 (dd, J=10.8 Hz, J=13.2, 1H), 4.15-4.18 (m, 1H), 3.65 (s, 3H),2.43 (s, 3H), 2.14-2.17 (m, 2H), 1.84-2.14 (m, 2H), 1.64-1.70 (m, 2H),1.33 (s, 9H).

Preparation of Compound of Formula I,R=1,1-dimethylethyl)-1-methyl-1H-pyrazol-5-yl (LUT013)

A mixture of compound 4C (250 mg, 425 umol, 1.0 eq) in HCl/MeOH (4 mL, 4M) was stirred for 1 hour at 20° C. TLC (dichloromethane:methanol=10:1,R_(f)=0.24) and LCMS (ET15300-18-P1A, product RT=2.384) showed thestarting material was consumed completely. The mixture was concentratedin reduce pressure at 40° C. The pH value was adjusted to 9 with aqueousNaHCO₃ and the aqueous phase was poured into ethyl acetate (10 mL). Themixture was stirred for 5 min. The mixture was filtered and the filtercake was washed with 10 mL of H₂O, dried in vacuum. The filter liquorwas extracted with ethyl acetate (10 mL, 6 mL). The combined organicphase was washed with brine (20 mL), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified byprep-HPLC (column: YMC-Actus Triart C18 100*30 mm*5 um; mobile phase:[water (10 mM NH₄HCO₃)-ACN]; B %: 40%-60%, 12 min) to afford LUT013 (150mg, 295 umol, 69.6% yield, 99.4% purity) as yellow solid.

¹H NMR: ET15300-18-P1A 400 MHz DMSO-d₆

δ 13.83 (br. s, 1H), 11.80 (s, 1H), 9.71 (s, 1H), 9.09 (s, 1H), 9.05 (s,1H), 8.73 (s, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.04 (d, J=2.8 Hz, 1H), 7.80(d, J=2.0 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.08 (d, J=6.0 Hz, 1H),6.89-6.92 (m, 1H), 6.05 (s, 1H), 3.54 (s, 3H), 2.36 (s, 3H), 1.26 (s,9H).

Example 3 Synthesis of Compound of Formula I,R=3-(trifluoromethoxy)phenyl (LUT014)—Laboratory Scale ProcessPreparation of Intermediate 3D-2

To a mixture of compound 3B-1 (2.00 g, 8.98 mmol, 1.0 eq) and compound3D-1 (1.91 g, 10.8 mmol, 1.2 eq) in isopropanol (20 mL) was added TFA(1.02 g, 8.98 mmol, 1.0 eq) in one portion at 20° C. under nitrogen. Themixture was stirred at 90° C. for 18 hours. LC-MS (ET15060-21-P1A1)showed the reaction was completed. The resulting suspension was cooledand the product was filtered off, washing with a small volume ofdichloromethane (10 mL) to give compound 3D-2 (3.00 g, 8.26 mmol, 91.9%yield) as yellow solid which was used for next step directly.

¹H NMR: ET15060-21-P1A1 400 MHz DMSO-d₆

9.68 (s, 1H), 8.71 (d, J=8.8 Hz, 1H), 8.15 (d, J=6.0 Hz, 1H), 8.03 (s,1H), 7.91 (dd, J=8.4, 1.2 Hz, 1H), 7.71 (d, J=8.4, Hz, 1H), 7.45 (t,J=8.4 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.90 (d, J=6.0 Hz, 1H), 2.48 (s,3H).

Preparation of Intermediate 3D

To a mixture of compound 3D-2 (3.00 g, 8.26 mmol, 1.0 eq) in ethanol (30mL) was added SnCl₂.2H₂O (9.32 g, 41.3 mmol, 5.0 eq) in one portion at20° C. under nitrogen. The mixture was stirred at 85° C. for 16 hours.LC-MS (ET15060-24-P1A) showed the reaction was completed. The darksolution was concentrated, diluted with DCM (30 mL), washed with aq.NaOH (1.30 mol/L, 40 mL). The mixture was stirred for 10 min andfiltered. The filter was separated and the aqueous phase was extractedwith DCM (20 mL). The combined organic phase was washed with brine (30mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum togive compound 3D (2.20 g, 6.60 mmol, 79.9% yield) as a red solid whichwas used for next step directly without further purification.

¹H NMR: ET15060-24-P1A1 400 MHz DMSO-d₆

9.14 (s, 1H), 8.13 (s, 1H), 7.92-7.99 (m, 2H), 7.66 (d, J=8.4 Hz, 1H),7.50 (d, J=6.0, Hz, 1H), 7.39 (t, J=8.4, Hz, 1H), 7.29 (s, J=8.4, 1H),6.88 (d, J=7.6, 1H), 5.53 (d, 2H), 2.28 (s, 3H).

Preparation of Intermediate 4D

To a mixture of compound 3 (850 mg, 2.84 mmol, 1.0 eq) and compound 3D(947 mg, 2.84 mmol, 1.0 eq) in tetrahydrofuran (8.50 mL) was added dropwise LiHMDS (1 M, 14.2 mL, 5.0 eq) at 0° C. under nitrogen. The mixturewas stirred at 0° C. for 1 hour. TLC (petroleum ether/ethyl acetate=1/1,R_(f)=0.48) showed the reaction was completed. The deep red reactionmixture was quenched with drop wise addition of water (1 mL—ice bathcooling) resulting in a light orange solution containing a white solidin suspension. The mixture was concentrated to a give yellow solid whichwas suspended in ethyl acetate (80 mL), dried (MgSO₄) and filteredthrough a plug of Celite to give a yellow solution and concentrated invacuum. The residue was suspended in MTBE (15 mL) and stirred for 12hours. The mixture was filtered and the filter cake was dried in vacuumto give compound 4D (1.50 g, 2.45 mmol, 86.2% yield) as yellow solid.

¹H NMR: ET15060-38-p1a1 400 MHz DMSO-d₆

11.77 (s, 1H), 9.75 (d, J=6.4 Hz, 1H), 9.64 (s, 1H), 9.19 (s, 1H), 9.06(s, 1H), 8.54 (d, J=8.4 Hz, 1H), 8.20 (s, 1H), 8.13 (dd, J=4.4, 1.6 Hz,1H), 8.03 (d, J=6.0 Hz, 2H), 7.69 (d, J=8.8 Hz, 1H), 7.49 (t, J=8.0 Hz,1H), 7.26 (d, J=6.0 Hz, 1H), 6.99 (dd, J=8.0, 4.4 Hz, 2H), 5.97 (d,J=10.0 Hz, 1H), 4.15 (d, J=12.0 Hz, 1H), 3.81-3.88 (m, 1H), 2.40-2.47(m, 4H), 2.06-2.16 (m, 3H), 1.83-1.86 (m, 1H).

Preparation of Compound of Formula I, R=3-(trifluoromethoxy)phenyl(LUT014)

Compound 4D (1.50 g, 2.45 mmol, 1.0 eq) was suspended in aqueous HCl(0.5 M, 44.1 mL, 9.0 eq) and heated to 100° C. and stirred for 2 hr. Thebulk of the solid dissolved to give a yellow solution. LC-MS(ET15060-42-P1A2) showed the reaction was completed. The hot solutionwas filtered, washing with boiling water (2×5.0 mL). The resultingsolution was cooled in an ice bath and product crystallized fromsolution as a yellow solid. pH value was adjusted to 9 with Na₂CO₃(solid). The mixture was stirred for 10 min and filtered and the filtercake was washed with water (5.0 mL) and collected. The solid was addeddichloromethane:methanol (10:1, 15 mL) and stirred for 5 min. Themixture was filtered and the filter cake was collected to give LUT014(150 mg, 274 umol, 11.2% yield, 96.7% purity) as a yellow solid.

¹H NMR: ET15060-42-P1A2 400 MHz DMSO-d₆

13.84 (s, 1H), 11.85 (s, 1H), 9.76 (s, 1H), 9.43 (s, 1H), 9.06 (s, 1H),8.74 (s, 1H), 8.43 (d, J=8.8 Hz, 1H), 8.12 (s, 1H), 8.05 (dd, J=4.4, 1.6Hz, 1H), 7.94-7.97 (m, 2H), 7.64 (d, J=8.8 Hz, 1H), 7.43 (t, J=8.4 Hz,1H), 7.21 (d, J=6.0 Hz, 1H), 6.92 (dd, J=8.0, 4.8 Hz, 2H), 2.38 (s, 3H).

Example 4 Synthesis of Compound of Formula I,R=3-(trifluoromethoxy)phenyl (LUT014 or C17071479-F) by an Improved,Scaled-Up Process

Example 3 discloses a process for the synthesis of the LUT014 compoundat laboratory scale.

An improved, scaled-up synthetic process for the preparation of LUT014was carried out at multi-Kg scale, in order to validate the improvedprocess at large scale production and provide material for clinicalstudies. The improved scaled-up process is disclosed in this example.

The improved scaled-up synthetic process produced 4,015 Kg LUT014, avery large scale-up, as compared to the above laboratory scale processof Example 3, which resulted in 150 mg. The flow diagram in FIG. 6depicts the improved scaled-up process for the preparation of LUT014(C17071479-F), its stages, amounts, yields and purities of theintermediates and of the LUT014 (C17071479-F) product.

This Example validates the improved scaled-up synthesis of the LUT014compound at kilogram scale in a multi-stage process followed bypurification by crystallization yielding a purified product of 99.3%purity.

Synthetic Stages of the Improved Scaled-Up Process for the Manufactureof Compound of Formula I, R=3-(trifluoromethoxy)phenyl (LUT014 orC17071479-1) Stage 1

Stage 2

Stage 3

Stage 4

Stage 5

Stage 6

C17071479-F (compound LUT014) of high purity (99.3%) and assay 99.9%)was obtained by this process.

Example 5 Synthesis of Compound of Formula I. R=3-chloro-4-fluorophenyl(LUT015) Preparation of Intermediate 3E-2

To a mixture of compound 3B-1 (2.00 g, 8.98 mmol, 1.0 eq) and compound3B-2 (1.57 g, 10.8 mmol, 1.2 eq) in isopropanol (20 mL) was added TFA(1.02 g, 8.98 mmol, 1.0 eq) in one portion at 20° C. under nitrogen. Themixture was stirred at 90° C. for 18 hours. TLC (petroleum ether:ethylacetate=3:1, R_(f)=0.43) showed the reaction was completed. The mixturewas cooled and the mixture was filtered. The filter cake was washed witha small volume of dichloromethane (10 mL) to give compound 3E-2 (3.10 g,crude) as yellow solid which was used for next step directly.

¹H NMR: ET15060-4-P1A1 400 MHz DMSO-d₆

10.75 (br. s, 1H), 8.91 (d, J=8.8 Hz, 1H), 7.96 (dd, J=6.4, 3.2 Hz, 1H),7.95 (d, J=6.4 Hz, 1H), 7.83 (d, J=8.8, Hz, 1H), 7.72-7.76 (m, 1H),7.49-7.55 (m, 1H), 6.95 (d, J=6.4 Hz, 1H), 2.50 (s, 3H).

Preparation of Intermediate 3E

To a mixture of compound 3E-2 (3.10 g, 9.34 mmol, 1.0 eq) in ethanol (30mL) was added SnCl₂.2H₂O (10.5 g, 46.7 mmol, 5.0 eq) in one portion at20° C. under nitrogen. The mixture was stirred at 85° C. for 16 hours.LCMS (ET15060-34-P1A1) showed the reaction was completed. The darksolution was concentrated, diluted with dichloromethane (30 mL), washedwith aq. NaOH (1.30 mol/L, 25.0 mL). The mixture was stirred for 10 minand filtered. The organic phase was separated and the aqueous phase wasextracted with dichloromethane (20 mL). The combined organic phase waswashed with brine (15 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum to give compound 3E (2.50 g, 8.29 mmol, 88.7%yield) as a red solid which was used for next step directly withoutfurther purification.

¹H NMR: ET15060-34-P1A1 400 MHz DMSO-d₆

9.01 (s, 1H), 8.26 (dd, J=6.8, 2.4 Hz, 1H), 7.89 (d, J=6.0 Hz, 1H),7.81-7.87 (m, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.45 (d, J=6.0, Hz, 1H), 7.30(t, J=8.8 Hz, 1H), 7.27 (d, J=8.4, 1H), 5.50 (s, 2H), 2.32 (s, 3H).

Preparation of Intermediate 4E

To a mixture of compound 3 (2.00 g, 6.68 mmol, 1.0 eq) and compound 3E(2.02 g, 6.68 mmol, 1.0 eq) in tetrahydrofuran (20 mL) was added dropwise LiHMDS (1 M, 33.4 mL, 5.0 eq) at 0° C. under nitrogen. The mixturewas stirred at 0° C. for 1 hour. TLC (petroleum ether:ethyl acetate,R_(f)=0.43) showed the reaction was completed. The deep red reactionmixture was quenched with drop wise addition of water (2 mL—ice bathcooling) resulting in a light orange solution containing a white solidin suspension. The mixture was concentrated to a give yellow solid whichwas suspended in ethyl acetate (200 mL), dried (MgSO₄) and filteredthrough a plug of Celite to give a yellow solution and concentrated invacuum. The residue was suspended in MTBE (30.0 mL) and stirred for 12h. The mixture was filtered and the filter cake was dried in vacuum togive compound 4E (2.00 g, 3.44 mmol, 51.5% yield) as a yellow solid.

¹H NMR: ET15060-39-P1A1 400 MHz DMSO-d₆

11.69 (s, 1H), 9.68 (d, J=1.6 Hz, 1H), 9.66 (s, 1H), 9.12 (s, 1H), 9.11(s, 1H), 8.44 (d, J=8.8 Hz, 1H), 8.30 (d, J=6.8 Hz, 1H), 8.07 (d, J=2.8Hz, 1H), 7.93-7.95 (m, 2H), 7.61-7.63 (m, 1H), 7.49 (t, J=8.0 Hz, 1H),7.37 (t, J=1.2 Hz, 1H), 7.16 (d, J=6.0 Hz, 1H), 6.93 (d, J=4.8 Hz, 1H),5.91 (d, J=9.2 Hz, 1H), 4.04-4.06 (m, 1H), 3.77 (t, J=12.0 Hz, 1H),2.34-2.41 (m, 6H), 2.02-2.10 (m, 3H), 1.76-1.79 (m, 1H).

Preparation of Compound of Formula I, R=3-chloro-4-fluorophenyl (LUT015)

Compound 4E (2.00 g, 3.44 mmol, 1.0 eq) was suspended in aqueous HCl(0.5 M, 62.0 mL, 9.0 eq) and heated to 100° C. and stirred for 2 hrs.The bulk of the solid dissolved to give a yellow solution. LCMS(ET15060-43-P1A2) showed the reaction was completed. The hot solutionwas filtered, washing with boiling water (2×10 mL). pH value wasadjusted to 9 with Na₂CO₃ (solid). The mixture was filtered and thefilter cake was purified by prep-TLC (petroleum ether:ethyl acetate=0:1,R_(f)=0.46) to give LUT015 (170 mg, 332 umol, 9.64% yield, 97.0% purity)as a yellow solid.

¹H NMR: ET15060-43-P1A1 400 MHz DMSO-d₆

13.84 (s, 1H), 11.84 (s, 1H), 9.75 (s, 1H), 9.34 (s, 1H), 9.06 (s, 1H),8.74 (s, 1H), 8.39 (d, J=8.4 Hz, 1H), 8.28 (dd, J=6.8, 2.8 Hz, 1H), 8.05(dd, J=4.4, 1.6 Hz, 1H), 7.94 (d, J=6.0 Hz, 1H), 7.85-7.88 (m, 1H), 7.63(d, J=8.8 Hz, 1H), 7.38 (t, J=9.2 Hz, 1H), 7.18 (d, J=6.0 Hz, 1H), 6.92(dd, J=8.0, 4.8 Hz, 1H), 2.38 (s, 3H).

Example 6 Synthesis of Compound of Formula I, R=2-fluoro-4-iodophenyl(LUT016) Preparation of Intermediate 3F-2

To a mixture of compound 3B-1 (2.00 g, 8.98 mmol, 1.0 eq) in isopropanol(20 mL) was added compound 3F-3 (2.55 g, 10.8 mmol, 1.2 eq) andtrifluoroacetic acid (1.02 g, 8.98 mmol, 665 uL, 1.0 eq) at 20° C. undernitrogen. The resulting mixture was heated to 90° C. and stirred at 90°C. for 16 h. TLC (petroleum ether:ethyl acetate=3:1, R_(f-SM)=0.43,R_(f-DP)=0.24) showed the reaction was completed. The reaction mixturewas filtered and filter cake was washed with dichloromethane (10 mL),the filter cake was collected and dried in vacuum to afford compound3F-2 (2.80 g, 6.62 mmol, 73.7% yield) as a light-yellow solid, which wasused for next step without further purification.

¹H NMR: ET15201-2-P1A 400 MHz MeOD

δ 8.71 (d, J=8.8 Hz, 1H), 7.91-7.95 (m, 2H), 7.84 (d, J=8.4 Hz, 1H),7.74 (d, J=7.2 Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H),2.62 (s, 3H).

Preparation of Intermediate 3F

To a mixture of compound 3F-2 (2.80 g, 6.62 mmol, 1.0 eq) in ethanol (28mL) was added SnCl₂.2H₂O (7.47 g, 33.1 mmol, 5.0 eq) at 20° C. undernitrogen. The resulting mixture was heated to 85° C. and stirred at 85°C. for 16 h. TLC (petroleum ether:ethyl acetate=2:1, R_(f-SM)=0.43,R_(f-DP)=0.30) showed the reaction was completed. The reaction mixturewas cooled to 20° C. and poured to 5 N NaOH aqueous (20 mL) and stirredfor 3 min, filtered and the filtrate was extracted with dichloromethane(20 mL, 15 mL). The combined organic phase was dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum to afford compound 3F (2.20g, crude) as red solid, which was used for next step without furtherpurification.

¹H NMR: ET15201-6-P1A 400 MHz DMSO-d₆

δ 7.74 (d, J=6.4 Hz, 1H), 7.61 (dd, J=8.0, 2.4 Hz, 1H), 7.44-7.52 (m,3H), 7.37 (d, J=6.8 Hz, 1H), 7.21 (d, J=6.8 Hz, 1H), 5.47 (s, 2H), 2.25(s, 3H).

Preparation of Intermediate 3F

To a mixture of compound 3 (1.00 g, 3.34 mmol, 1.0 eq) and compound 3F(1.31 g, 3.34 mmol, 1.0 eq) in tetrahydrofuran (10 mL) was added LiHMDS(1 M, 16.7 mL, 5.0 eq) at 0° C. under nitrogen. The resulting mixturewas stirred at 0° C. for 1 h. TLC (petroleum ether:ethyl acetate=2:1,R_(f-SM)=0.25, R_(f-DP)=0.40) showed the reaction was completed. Thereaction mixture was quenched with dropwise addition of ice-water (2 mL)at 0° C. while resulting in a light orange solution containing a whitesolid in suspension. The mixture was concentrated to give a yellow solidwhich was suspended in ethyl acetate (50 mL), dried with Na₂SO₄,filtered through a plug of Celite to give a yellow solution and wasconcentrated in vacuum. The residue was washed with methyl tert-butylether (20 mL), filtered to afford the filter cake and filter cake wasdried in vacuum to give compound 4F (1.10 g, 1.64 mmol, 49.0% yield) asa light-yellow solid.

¹H NMR: ET15201-10-P1A1 400 MHz DMSO-d₆

δ 11.68 (s, 1H), 9.63-9.67 (m, 1H), 9.08-9.12 (m, 2H), 8.98 (s, 1H),8.30 (d, J=8.8 Hz, 1H), 8.05-8.06 (m, 1H), 7.79 (d, J=6.0 Hz, 1H), 7.66(dd, J=8.2, 2.0 Hz, 1H), 7.54-7.60 (m, 2H), 7.44-7.46 (m, 2H), 7.11 (d,J=6.0 Hz, 1H), 6.91 (q, J=4.4 Hz, 1H), 5.89 (d, J=11.2 Hz, 1H), 4.07 (d,J=12.8 Hz, 1H), 3.74-3.80 (m, 1H), 2.36 (s, 3H), 2.05 (t, J=13.6 Hz,2H), 1.63-1.68 (m, 3H), 1.11 (s, 2H).

Preparation of Compound of Formula I, R=2-fluoro-4-iodophenyl (LUT016)

Compound 4F (1.10 g, 1.64 mmol, 1.0 eq) was suspended in HCl (0.5 M, 29mL, 9.0 eq) at 20° C. under nitrogen. The mixture was heated to 100° C.and stirred at 100° C. for 1 h. LCMS (ET15201-12-P1A1) showed thereaction was completed. The hot solution was filtered, washing withboiling water (2×20 mL). The resulting solution was cooled in an icebath and product was crystallized from solution as a yellow solid. Thesolid was filtered and added to saturated aq. NaCO₃ (100 mL). Themixture was stirred for 10 min and filtered, the filtered cake waswashed with water (50 mL) and collected as crude product. The crudeproduct was purified by prep-HPLC (column: Waters Xbridge 150*25 5 u;mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %: 50%-80%, 11 min) toafford LUT016 (125 mg, 212 umol, 12.9% yield, 99.6% purity) as a yellowsolid

¹HNMR: ET15201-12-P1A1 400 MHz DMSO-d₆

δ 13.81 (s, 1H), 11.79 (s, 1H), 9.71 (s, 1H), 9.04 (s, 2H), 8.72 (s,1H), 8.24 (d, J=8.4 Hz, 1H), 8.04 (q, J=2.0 Hz, 1H), 7.78 (d, J=6.0 Hz,1H), 7.65 (d, J=9.6 Hz, 1H), 7.57 (q, J=8.4 Hz, 2H), 7.44 (t, J=8.4 Hz,1H), 7.11 (d, J=6.0 Hz, 1H), 6.90 (d, J=4.8 Hz, J=2.8 Hz, 1H), 2.36 (s,3H).

Example 7 Synthesis of Compound of Formula I,R=4-chloro-3-(trifluoromethyl)phenyl (LUT017) Preparation ofIntermediate 3G-2

To a mixture of compound 3B-1 (2.00 g, 8.98 mmol, 1.0 eq) and compound3G-1 (2.11 g, 10.8 mmol, 1.2 eq) in isopropanol (20 mL) was added TFA(1.02 g, 8.98 mmol, 1.0 eq) in one portion at 20° C. under nitrogen. Themixture was stirred at 90° C. for 18 hours. LCMS (ET15060-19-P1A1)showed the reaction was completed. The mixture was cooled to 20° C. andthe mixture was filtered. The filter cake was washed withdichloromethane (10 mL) and collected as product (3.20 g, 8.38 mmol,93.3% yield) as a white solid which was used for next step directlywithout further purification.

¹H NMR: ET15060-3-P1A1 400 MHz DMSO-d₆

10.21 (s, 1H), 8.81 (d, J=8.8 Hz, 1H), 8.42 (dd, J=2.4 Hz, 1H), 8.28 (d,J=2.0 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.12 (d, J=6.0 Hz, 1H), 7.79 (d,J=8.8 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 6.98 (d, J=6.0 Hz, 1H), 2.50 (s,3H).

Preparation of Intermediate 3G

To a mixture of compound 3G-2 (3.20 g, 8.38 mmol, 1.0 eq) in ethanol (30mL) was added SnCl₂.2H₂O (9.46 g, 41.9 mmol, 5.0 eq) in one portion at20° C. under nitrogen. The mixture was stirred at 85° C. for 16 hours.LCMS (ET15060-22-P1A) showed the reaction was completed. The darksolution was concentrated, diluted with dichloromethane (50 mL), washedwith aq. NaOH (1.30 mol/L, 50 mL). The mixture was stirred for 10 minand filtered. The filter was separated and the aqueous phase wasextracted with dichloromethane (20 mL). The combined organic phase waswashed with brine (30 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum to give compound 3G (2.50 g, 7.11 mmol, 84.8%yield) as a yellow solid.

1H NMR: ET15060-22-p1a1 400 MHz DMSO-d₆

9.34 (s, 1H), 8.58 (d, J=8.8, 1H), 8.37 (d, J=8.8 Hz, 1H), 7.99 (d,J=6.0 Hz, 1H), 7.65-7.70 (m, 1H), 7.57 (d, J=6.0 Hz, 1H), 7.35 (d,J=8.4, 1H), 5.60 (s, 2H), 2.30 (s, 3H).

Preparation of Intermediate 4G

To a mixture of compound 3 (2.00 g, 6.68 mmol, 1.0 eq) and compound 3G(2.35 g, 6.68 mmol, 1.0 eq) in tetrahydrofuran (20 mL) was added dropwise LiHMDS (1 M, 33.4 mL, 5 eq) at 0° C. under nitrogen. The mixturewas stirred at 0° C. for 1 hour. TLC (petroleum ether:ethyl acetate=1:1,R_(f)=0.45) showed the reaction was completed. The deep red reactionmixture was quenched with drop wise addition of ice-water (3 mL)resulting in a light orange solution containing a white solid insuspension. The mixture was concentrated to a give yellow solid whichwas suspended in ethyl acetate (150 mL), dried (MgSO₄) and filteredthrough a plug of Celite to give a yellow solution and concentrated invacuum. The residue was suspended in MTBE (150 mL) and stirred for 12hrs. The mixture was filtered and the filter cake was dried in vacuum togive compound 4G (1.50 g, 1.47 mmol, 22.1% yield, 62.0% purity) as a redsolid. (LCMS:ET15060-32-P1A1)

¹H NMR: ET15060-32-P1A1 400 MHz DMSO-d₆

11.69 (s, 1H), 9.66 (d, J=2.0 Hz, 1H), 9.64 (s, 1H), 9.10 (s, 1H), 8.96(s, 1H), 8.50 (d, J=2.4 Hz, 1H), 8.33-8.41 (m, 2H), 8.05 (d, J=2.8 Hz,1H), 7.96 (d, J=6.0 Hz, 1H), 7.62-7.64 (m, 2H), 7.20-7.22 (m, 1H), 6.94(d, J=4.8 Hz, 1H), 5.88 (d, J=10.8 Hz, 1H), 4.03-4.06 (m, 1H), 3.73-3.79(m, 1H), 2.37 (s, 3H), 1.99-2.07 (m, 2H), 1.62-1.80 (m, 3H).

Preparation of Compound of Formula I,R=4-chloro-3-(trifluoromethyl)phenyl (LUT017)

Compound 4G (1.50 g, 2.38 mmol, 1.0 eq) was suspended in aqueous HCl(0.5 M, 28.5 mL, 6.0 eq) and heated to 100° C. and stirred for 2 hrs.The bulk of the solid dissolved to give a yellow solution. LCMS(ET15060-36-P1A2) showed the reaction was completed. The hot solutionwas filtered, washing with boiling water (2×10 mL). pH value wasadjusted to 9 with Na₂CO₃ (solid). The mixture was filtered and thefilter cake was purified by prep-TLC (petroleum ether:ethyl acetate=0:1,R_(f)=0.65) to give 0.3 g solid. The solid was purified by prep-HPLC(column: YMC-Actus Triart C18 100*30 mm*5 um; liquid phase: [A-10 mMNH₄HCO₃ in H₂O; B-ACN]B %: 50%-95%, 12 min]) to give LUT017 (150 mg, 269umol, 11.3% yield, 98.0% purity) as a yellow solid.

¹H NMR: ET15060-36-P1A1 400 MHz DMSO-d₆

13.84 (br. s, 1H), 11.83 (br. s, 1H), 9.73 (s, 1H), 9.60 (s, 1H), 9.06(s, 1H), 8.74 (s, 1H), 8.52 (d, J=2.4 Hz, 1H), 8.42 (d, J=8.8 Hz, 1H),8.36 (d, J=2.4 Hz, 1H), 8.05 (dd, J=4.8, 1.2 Hz, 1H), 7.98 (d, J=6.0 Hz,1H), 7.66 (dd, J=8.8, 2.8 Hz, 1H), 7.23 (d, J=6.0 Hz, 1H), 6.92 (dd,J=7.6, 4.8 Hz, 2H), 2.39 (s, 3H).

Example 8 Synthesis of Compound of Formula I, R=3,5-dihydroxyphenyl(LUT019) Preparation of Intermediate 3H-2

To a mixture of compound 3B-1 (3.00 g, 13.5 mmol, 1.0 eq) in isopropanol(30 mL) was added compound 3H-3 (2.48 g, 16.2 mmol, 1.2 eq) andtrifluoroacetic acid (1.54 g, 13.5 mmol, 996 mL, 1.0 eq) at 20° C. undernitrogen. The resulting mixture was heated to 90° C. and stirred at 90°C. for 16 h. TLC (petroleum ether:ethyl acetate=3:1, R_(f-SM)=0.43,R_(f-DP)=0.24) showed the reaction was completed. The reaction mixturewas filtered and filter cake was washed with dichloromethane (10 mL),the filter cake was collected and dried in vacuum to afford compound3H-2 (4.50 g, 13.3 mmol, 98.4% yield) as a yellow solid, which was usedfor next step without further purification.

¹H NMR: ET15201-5-P1A 400 MHz MeOD

δ 8.75 (d, J=8.4 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.62 (d, J=7.2 Hz,1H), 7.06 (d, J=7.2 Hz, 1H), 6.74 (s, 2H), 6.67 (s, 1H), 3.86 (s, 6H),2.6 (s, 3H).

Preparation of Intermediate 3H

To a mixture of compound 3H-2 (4.50 g, 13.3 mmol, 1.0 eq) in ethanol (45mL) was added SnCl₂.2H₂O (15.0 g, 66.3 mmol, 5.0 eq) at 20° C. undernitrogen. The resulting mixture was heated to 85° C. and stirred at 85°C. for 16 h. TLC (petroleum ether:ethyl acetate=3:1, R_(f-SM)=0.43,R_(f-DP)=0.30) showed the reaction was completed. The reaction mixturewas cooled to 20° C. and poured to 5 N NaOH aqueous (20 mL) and stirredfor 5 min, filtered and the filtrate was extracted with dichloromethane(20 mL, 15 mL). The combined organic phase was dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum to afford compound 3H (3.80g, crude) as a red solid, which was used for next step without furtherpurification.

¹H NMR: ET15201-7-P1A 400 MHz DMSO-d₆

δ 8.77 (s, 1H), 8.15 (s, 1H), 7.90 (d, J=6.0 Hz, 1H), 7.63 (d, J=8.4 Hz,1H), 7.41 (d, J=6.4 Hz, 1H), 7.23-7.27 (m, 3H), 6.12 (t, J=2.0 Hz, 1H),5.48 (s, 2H), 3.74 (s, 6H), 2.26 (s, 3H).

Preparation of Intermediate 4H

To a mixture of compound 3 (2.00 g, 6.68 mmol, 1.0 eq) and compound 3H(2.07 g, 6.68 mmol, 1.0 eq) in tetrahydrofuran (10 mL) was added LiHMDS(1 M, 33 mL, 5.0 eq) at 0° C. under nitrogen. The resulting mixture wasstirred at 0° C. for 1 h. TLC (petroleum ether:ethyl acetate=2:1,R_(f-SM)=0.43, R_(f-DP)=0.30) showed the reaction was completed. Thereaction mixture was quenched with dropwise addition of ice-water (2.0mL) at 0° C. while resulting in alight orange solution containing awhite solid in suspension. The mixture was concentrated to give a yellowsolid which was suspended in ethyl acetate (50 mL), dried with Na₂SO₄,filtered through a plug of Celite to give a yellow solution and wasconcentrated in vacuum. The residue was washed with methyl tert-butylether (20 mL), filtered to afford the filter cake and filter cake wasdried in vacuum to afford compound 4H (2.30 g, crude) as a brown solid.

¹H NMR: ET15201-13-P1A 400 MHz DMSO-d₆

δ 11.69 (s, 1H), 9.66 (dd, J=6.0, 2.0 Hz, 1H), 9.11 (d, J=8.0 Hz, 1H),8.98 (s, 1H), 8.41 (d, J=8.4 Hz, 1H), 8.04-8.07 (m, 1H), 7.94 (d, J=6.0Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.27 (d, J=2.0 Hz, 2H), 7.13 (d, J=5.6Hz, 1H), 6.89-6.93 (m, 1H), 6.15 (d, J=2.0 Hz, 1H), 5.89 (dd, J=9.2, 2.0Hz, 1H), 4.07 (d, J=13.2 Hz, 1H), 3.77 (s, 6H), 2.36 (s, 3H), 1.99-2.08(m, 2H), 1.63-1.81 (m, 3H), 1.10 (s, 1H).

Preparation of Compound of Formula I, R=3,5-dihydroxyphenyl (LUT019)

To a solution of compound 4H (1.20 g, 2.04 mmol, 1.0 eq) indichloromethane (10 mL) was added BBr₃ (5.11 g, 20.4 mmol, 2.0 mL, 10.0eq) at 0° C. under nitrogen. The resulting mixture was warmed to 25° C.and stirred for 16 h. LCMS (ET15201-18-P1A2) showed the reaction wascompleted. The reaction mixture was concentrated in vacuum and poured insaturated NH₄Cl aqueous (10 mL), dried with anhydrous Na₂SO₄, filteredand concentrated in vacuum. The residue was purified by prep-HPLC(column: Waters Xbridge 150*25 5 u; mobile phase: [water (0.05% ammoniahydroxide v/v)-MeOH]; B %: 15%-50%, 11 min) to afford product LUT019(20.0 mg, 40.8 umol, 2.00% yield, 97.1% purity) as a yellow solid.

¹HNMR: ET15201-18-P1A2 400 MHz MeOD

δ 9.60 (br. s, 1H), 9.02 (s, 1H), 8.53 (s, 1H), 8.23 (d, J=8.8 Hz, 1H),7.98 (dd, J=3.2, 1.6 Hz, 1H), 7.74 (d, J=6.0 Hz, 1H), 7.59 (d, J=8.4 Hz,2H), 7.23 (d, J=7.2 Hz, 1H), 6.90-6.93 (m, 1H), 6.61 (d, J=2.4 Hz, 2H),6.07 (q, J=2.0 Hz, 1H), 2.43 (s, 3H).

Example 9 Preparation of Compound of Formula L. R=phenyl-3-sulfonamide(LUT020) Preparation of Intermediate 3I-2

To a mixture of compound 3B-1 (2.00 g, 8.98 mmol, 1.0 eq) and 3I-1 (1.86g, 10.8 mmol, 1.2 eq) in isopropanol (50 mL) was added TFA (3.07 g, 26.9mmol, 3.0 eq) in one portion at 20° C. under nitrogen. The mixture wasstirred at 90° C. for 18 hours. LCMS (ET15060-20-P1A1) showed thereaction was completed. The mixture was cooled to 20° C. and the mixturewas filtered. The filter cake was washed with dichloromethane (10 mL)and collected to give product compound 3I-2 (3.20 g, 8.93 mmol, 99.4%yield) as a white solid which was used for next step directly withoutfurther purification.

¹H NMR: ET15060-5-P1A1 400 MHz DMSO-d₆

10.19 (s, 1H), 8.82 (d, J=8.8 Hz, 1H), 8.31 (s, 1H), 8.06 (d, J=6.4 Hz,1H), 7.79 (d, J=8.8, Hz, 1H), 7.54-7.59 (m, 1H), 7.40 (s, 1H), 6.95 (d,J=6.4 Hz, 1H), 2.50 (s, 3H).

Preparation of Intermediate 31

To a mixture of compound 3I-2 (3.20 g, 8.93 mmol, 1.0 eq) in ethanol (32mL) was added SnCl₂.2H₂O (10.1 g, 44.7 mmol, 5.0 eq) in one portion at20° C. under nitrogen. The mixture was stirred at 85° C. for 16 hours.LCMS (ET15060-23-P1A) showed the reaction was completed. The darksolution was concentrated, diluted with dichloromethane (50 mL), washedwith aq. NaOH (1.30 mol/L, 20 mL). The mixture was stirred for 10 minand filtered. The filter was separated and the aqueous phase wasconcentrated in vacuum. The solid was dissolved indichloromethane:methanol (8:1, 200 mL). The mixture was filtered and thefiltrate was concentrated in vacuum to give compound 3I (2.50 g, 7.61mmol, 85.3% yield) as a red solid.

¹H NMR: ET15060-23-P1A1 400 MHz DMSO-d₆

8.98 (s, 1H), 8.20 (s, 1H), 7.94 (s, J=6.8 Hz, 1H), 7.84 (d, J=6.0 Hz,1H), 7.66 (dd, J=8.8 Hz, 1H), 7.38 (d, J=6.0, Hz, 1H), 7.26-7.28 (m,2H), 7.21 (d, J=8.4, 1H), 5.43 (s, 2H), 2.23 (s, 3H).

Preparation of Intermediate 41

To a mixture of compound 3 (2.00 g, 6.68 mmol, 1.0 eq) and compound 3I(2.19 g, 6.68 mmol, 1.0 eq) in tetrahydrofuran (20 mL) was added dropwise LiHMDS (1 M, 33.4 mL, 5.0 eq) at 0° C. under nitrogen. The mixturewas stirred at 0° C. for 1 hour. TLC (petroleum ether:ethyl acetate=0:1,R_(f)=0.20) showed the reaction was completed. The deep red reactionmixture was quenched with drop wise addition of water (3 mL—ice bathcooling) resulting in a light orange solution containing a white solidin suspension. The mixture was concentrated to a give yellow solid whichwas suspended in ethyl acetate (100 mL), dried (MgSO₄) and filteredthrough a plug of Celite to give a yellow solution and concentrated invacuum. The residue was suspended in MTBE (30 mL) and stirred for 12 h.The mixture was filtered and the filter cake was dried in vacuum to givecompound 41 (2.20 g, crude) as a yellow solid.

¹H NMR: ET15060-40-P1A1 400 MHz DMSO-d₆ (crude)

Preparation of Compound of Formula I, R=phenyl-3-sulfonamide (LUT020)

Compound 41 (2.00 g, 3.29 mmol, 1.0 eq) was suspended in HCl/EtOAc (4 M,41.1 mL, 50 eq) and stirred at 30° C. for 2 hrs. LCMS (ET15060-45-P1A1)showed the reaction was completed. The solution was filtered, washedwith ethyl acetate (2×10 mL). The solid was added water (15 mL). pHvalue was adjusted to 9 with Na₂CO₃ (solid). The mixture was filteredand the filter cake was purified by prep-TLC (petroleum ether:ethylacetate=0:1, R_(f)=0.10) to give 0.19 g solid. The solid was purified byprep-HPLC (column: YMC-Actus Triart C18 100*30 mm*5 um; liquid phase:[A-10 mM NH₄HCO₃ in H₂O; B-ACN]B %: 25%-55%, 12 min] to give LUT020(85.0 mg, 159 umol, 4.83% yield, 98.0% purity) as a yellow solid.

¹H NMR: ET15060-45-P1A2 400 MHz DMSO-d₆

13.83 (s, 1H), 11.82 (s, 1H), 9.73 (s, 1H), 9.49 (s, 1H), 9.07 (s, 1H),8.74 (s, 1H), 8.45-8.47 (m, 2H), 8.16 (d, J=8.8 Hz, 1H), 8.05 (dd,J=4.8, 1.6 Hz, 1H), 7.95 (d, J=6.0 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.51(t, J=8.0 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.33 (s, 2H), 7.19 (d, J=6.0Hz, 1H), 6.91 (dd, J=8.0, 4.8 Hz, 1H), 2.38 (s, 3H).

Example 10 BRaf Inhibitory Activity of the Compounds of PresentDisclosure

In this assay, the BRaf inhibitory activity of the compound of formulaI, where R is 3-(trifluoromethoxy)phenyl (LUT014) and Vemurafenib, aknown inhibitor of BRAF containing V600E mutation was tested onwild-type BRaf and BRAF containing V600E mutation. A known inhibitor ofBRaf and CRaf, GW5074, was included in the assay as a control. LUT014and Vemurafenib were tested in 10-dose IC50 mode with a 3-fold serialdilution starting at 10 μM. Control Compound, GW5074, was tested in10-dose IC50 mode with 3-fold serial dilution starting at 20 μM.Reactions were carried out at 10 μM ATP.

The IC50 values obtained in this assay are shown in the table below.

TABLE 3 Compound IC50* (M): Compound ID BRAF BRAF (V600E) Lut0141.17E−08 1.33E−08 Vemurafenib 2.87E−09 4.00E−08 GW5074 1.99E−08 5.87E−09

Example 11 Phosphorylation of ERK in Primary Human Keratinocytes GeneralProcedure

Without wishing to be bound by theory, the inventor believeskeratinocytes is likely the site of the cutaneous side-effects, and theinhibition of EGFR and/or its downstream effectors (MAPK, MEK, PI3K, andthe like) in keratinocytes is likely the mechanism underlying this sideeffect. In this experiment, the effect of the compounds of presentdisclosure on ERK phosphorylation in human keratinocytes was studied.Phosphorylation of ERK indicates its activation.

Human normal keratinocyte cells HEKa were purchased from Gibco Rheniumand seeded in 10 cm dishes (300,000 cells/dish) and incubated overnightat 37° C., 5% CO₂. Next morning, the medium was replaced to a starvationmedium for 2 hours and then the cells were treated for 2 additionalhours with the test compounds. Post incubation, the cells were lyzedwith RIPA and the protein extracts were analyzed by western blot forPhospho-ERK and total ERK. Untreated cells and 0.10% DMSO treated cellswere used as negative control. HKGS growth factors was used as apositive control.

Western blot: 7.5 μg of total extract was loaded on 10% acrylamide gel.Following transfer, the membranes were blocked with TBST/5% skimmed milkand then incubated with Mouse anti Phospho-ERK (1:1000 in TBST 5% BSA,ON at 4° C.) and goat anti Mouse HRP (1:10,000 in TBST 5% BSA, 1-hourRT). The membranes were exposed using SuperSignal West PicoChemiluminescent Substrate.

The HRP was then inactivated by incubating the membranes for 1 hour with0.5% sodium azide Following washes and ECL exposure in order to ensureabsence of signal, the membranes were re-blocked for 15 min with TBST/5%skimmed milk and then incubated with Rabbit anti total ERK2 (1:500 inTBST 5% BSA, ON at 4° C.), goat anti Rabbit HRP (1:5,000 in TBST 5% BSA,1-hour RT) and finally exposed using the SuperSignal West PicoChemiluminescent Substrate. The films were scanned and the signal werequantified using ImageJ software. The results were calculated asPhospho-ERK/total ERK.

Example 12 ERK Phosphorylation Induced by the Compounds of PresentDisclosure—LUT014, LUT015, LUT017

HEKa cells were treated with LUT014, LUT015, LUT017, and Vemurafenib at0.3 μM and 1 μM as described in Example 11 and the Western blot analysisof HEKa cell lysates was carried out. HKGS growth factors was used as apositive control. FIG. TA shows Phospho-ERK (upper panel) and total ERK(lower panel) upon treatment with 0.3 μM of the test compounds. FIG. 1Bshows the densitometric analysis of blots in FIG. TA based on thecalculation of Phospho-ERK/total ERK ratio. FIG. 1C shows Phospho-ERK(upper panel) and total ERK (lower panel) upon treatment with 1 μM ofthe test compounds. FIG. 1D shows the densitometric analysis of blots inFIG. 1C based on the calculation of Phospho-ERK/total ERK ratio.

Example 13 ERK Phosphorylation Induced by the Compounds LUT012, LUT016,and C-1

HEKa cells were treated with LUT012, LUT016, and the knowncompounds—Vemurafenib and C-1 (old batch and new batch) at 0.3 μM and 1μM as described in Example 11 and the Western blot analysis of HEKa celllysates was carried out. HKGS growth factors was used as a positivecontrol. Compound C-1 has the following structure:

FIG. 2A shows Phospho-ERK (upper panel) and total ERK (lower panel) upontreatment with 0.3 μM of the test compounds. FIG. 2B shows thedensitometric analysis of blots in FIG. 2A based on the calculation ofPhospho-ERK/total ERK ratio. FIG. 2C shows Phospho-ERK (upper panel) andtotal ERK (lower panel) upon treatment with 1 μM of the test compounds.FIG. 2D shows the densitometric analysis of blots in FIG. 2C based onthe calculation of Phospho-ERK/total ERK ratio.

Example 14 ERK Phosphorylation Induced by the Compounds LUT012, LUT013,LUT014, LUT015, LUT016, LUT017, LUT020 and C-1

HEKa cells were treated with Vemurafenib, C-1, LUT012, LUT013, LUT014,LUT015, LUT016, LUT017 and LUT020 at 0.3 μM and 1 μM as described inExample 11 and the Western blot analysis of HEKa cell lysates wascarried out. HKGS growth factors was used as a positive control. FIG. 3Ashows Phospho-ERK (upper panel) and total ERK (lower panel) upontreatment with 0.3 μM of the test compounds. FIG. 3B shows Phospho-ERK(upper panel) and total ERK (lower panel) upon treatment with 1 μM ofthe test compounds. FIG. 3C shows the densitometric analysis of blots inFIGS. 3A and 3B based on the calculation of Phospho-ERK/total ERK ratio.

Example 15

ERK Phosphorylation Induced by the Novel Compounds LUT014, LUT017 vs.C-1

HEKa cells were treated with C-1, LUT014, and LUT017 at a concentrationof 0.003 μM, 0.03 μM, and 0.3 μM as described in Example 11 and theWestern blot analysis of HEKa cell lysates was carried out. HKGS growthfactors was used as a positive control. FIG. 4A shows Phospho-ERK (upperpanel) and total ERK (lower panel) upon treatment with 0.003 μM, 0.03μM, and 0.3 μM of the test compounds. FIG. 4B shows the densitometricanalysis of blots in FIG. 4A based on the calculation ofPhospho-ERK/total ERK ratio.

Example 16 Effect of the Compounds—LUT012, LUT013, LUT014, LUT015,LUT016, LUT017, LUT-019, LUT020, C-1, and Vemurafenib—on Proliferationof MIA PaCa Cells

In this example, effect of the compounds on proliferation of MIA PaCa2K-ras cells was studied. It was expected that the compounds that induceERK phosphorylation would also induce proliferation of Mia PaCa cells.

The cells were seeded in starvation medium at 5000 cells/well in a 96wells plate for 24 hours at 37° C., 5% CO₂. The tested compounds wereadded at different concentrations ranging from 0.002 μM to 10 μM. Thecontrols were untreated cells and vehicle of 0.1% DMSO. The cells wereincubated at 37° C., 5% CO₂, for 72 hours and then the proliferation wastested using the ATPlite proliferation kit (Perkin-Elmer). Each resultrepresents an average of 6 wells. The results are presented as thepercent of over-proliferation compared to the DMSO control. See FIG. 5.

The concentration of the compounds that provided the highestproliferation was compared to DMSO. DMSO was calculated as 100%. After72 hours, % proliferation compared to the DMSO control induced by C-1was 30%, LUT013 was 173%, LUT014 was 116%, LUT015 was 29%, LUT016 was110%, LUT017 was 174%, LUT012 was 20%, LUT019 was 7%, and LUT020 was12%. Vemurafenib showed 12% proliferation compared to DMSO.

Example 17 Kinase Selectivity Assay Study of Compound I,R=3-(Trifluoromethoxy)Phenyl (LUT014) Compound Preparation and AssayControls

All compounds were prepared to 50× final assay concentration in 100%DMSO. This working stock of the compound was added to the assay well asthe first component in the reaction, followed by the remainingcomponents. In the standard KinaseProfiler™ service, there is nopre-incubation step between the compound and the kinase prior toinitiation of the reaction. The positive control wells contain allcomponents of the reaction, except the compound of interest; however,DMSO (at a final concentration of 2%) is included in these wells tocontrol for solvent effects. The blank wells contain all components ofthe reaction, with a reference inhibitor replacing the compound ofinterest. This abolishes kinase activity and establishes the base-line(0% kinase activity remaining). The results are shown in Table 4.

TABLE 4 Kinase selectivity assay study of compound of formula I, R =3-(trifluoromethoxy)phenyl (LUT014) Lut014 @ 0.01 μM Lut014 @ 1 μMAbl(h) 92 25 ALK(h) 150 83 AMPKα1(h) 106 114 ASK1(h) 109 99 Aurora-A(h)95 97 CaMKI(h) 101 97 CDK1/cyclinB(h) 113 102 CDK2/cyclinA(h) 106 95CDK6/cyclinD3(h) 100 103 CDK7/cyclinH/MAT1(h) 105 109 CDK9/cyclin T1(h)110 98 CHK1(h) 100 114 CK1γ1(h) 94 101 CK2α2(h) 98 92 c-RAF(h) 105 30DRAK1(h) 99 117 eEF-2K(h) 95 106 EGFR(h) 98 100 EphA5(h) 99 56 EphB4(h)93 38 Fyn(h) 103 95 GSK3β(h) 105 98 IGF-1R(h) 88 86 IKKα(h) 105 105IRAK4(h) 94 109 JAK2(h) 126 118 KDR(h) 96 79 LOK(h) 98 83 Lyn(h) 101 46MAPKAP-K2(h) 110 103 MEK1(h) 98 105 MKK7β(h) 100 103 MLK1(h) 109 112Mnk2(h) 112 107 MSK2(h) 92 96 MST1(h) 98 112 mTOR(h) 100 96 NEK2(h) 98125 p70S6K(h) 108 97 PAK2(h) 95 111 PDGFRβ(h) 98 103 Pim-1(h) 96 89PKA(h) 114 106 PKBα(h) 102 105 PKCα(h) 102 107 PKCθ(h) 106 109 PKG1α(h)99 111 Plk3(h) 85 87 PRAK(h) 101 103 ROCK-I(h) 107 107 Rse(h) 106 113Rsk1(h) 106 112 SAPK2a(h) 97 54 SRPK1(h) 105 100 TAK1(h) 91 97 PI3Kinase (p110_(β)/p85_(α))(h) 101 95 PI3 Kinase (p120_(γ))(h) 96 83 PI3Kinase (p110_(δ)/p85_(α))(h) 96 94 PI3 Kinase (p110_(α)/p85_(α))(h) 9284

Example 18 Screening of the Compounds for Photo-Toxicity

Certain BRaf inhibitors are known to exhibit photo-toxicity. Therefore,the compounds of the present disclosure were screened for phototoxicityusing the 3T3 natural red uptake assay.

In brief, BALB/c-3T3 mouse fibroblasts (originally obtained from ATCC)were seeded in 96-well plates at 12,000 cells per well, and grown for 24hr. Test compounds and the positive control (chlorpromazine) weresolubilized and serially diluted in DMSO. The negative control(histidine) was solubilized and diluted in HBSS. A dilution for all testarticles was then made into HBSS at the final testing concentrations. Atthe start of the assay, the growth medium was removed from the platesand replaced with test agent dilution. Six replicates were used for eachconcentration. Cells were incubated in the dark with test article for 1h, exposed to UVA light (2.5 J/cm2 over 18 min) and incubated 24 hrs. inthe dark. A parallel non-irradiated plate was treated similarly, exceptit was stored in the dark, rather than illuminated.

For Neutral Red staining, medium was removed and fresh medium containing25 μg/mL of Neutral Red (Sigma) was added. After three hours incubation,the cells were washed with PBS, and the cellular dye was solubilizedwith 10% acetic acid in 50% ethanol. Cellular Neutral Red was measuredby its absorbance at 540 nm.

Data analysis: An IC50 (concentration that causes 50% reduction inviability) was calculated for each condition by linear interpolation.

A Photo-Irritation Factor (PIF) was calculated:PIF=IC50(−Irr)/IC50(+Irr)

PIF>5 indicates phototoxicity; 2<PIF<5 indicates probable phototoxicity;PIF<2 indicates no phototoxicity

In addition, the Mean Photo Effect (MPE) was calculated by comparison ofthe complete concentration-response curves. MPE is a weighted average ofthe difference in response of equivalent doses normalized by the shiftin IC50.

MPE>0.15 indicates phototoxicity; 0.1<MPE<0.15 indicates probablephototoxicity; MPE<0.1 indicates no phototoxicity.

TABLE 5 Assessment of the Photo-toxicity Cell Viability IC50 Minus PlusUVA UVA Mean Mean Test Article (μg/ml) (μg/ml) PIF MPE CommentHistidine >1000 >1000 1 0.036 Non Phototoxic Chlorpromazine 31.0 0.9831.6 0.477 Phototoxic C-15 25.7 1.31 19.6 0.241 Phototoxic C-19 >62.50.18 >312.5 0.571 Phototoxic C-1 14 18.12 0.8 −0.011 Non Phototoxic

C-15 and C-19 were showed phototoxicity. C-1 and LUT-104 did not showphototoxicity.

Example 19 In Vitro Effect of LUT014 on Phospho-ERK FollowingAdministration of EGFR Inhibitors

HEKa cells were treated with LUT014 and EGFR inhibitors, erlotinib andcetuximab, as described in Example 11. HKGS was used as a positivecontrol. The effect of LUT014 and EGFR inhibitors on phospho-ERK wasmeasured by Western blot as described in Example 11.

FIGS. 7A-7C and Table 6 shows the results of the effect of LUT014 onPhospho-ERK following administration of EGFR inhibitors.

TABLE 6 The effect of LUT014 and EGFRI on phospho-ERK phospho Totalphospho/ % of Gel #3 ERK ERK total ratio control DMSO 539.971 7316.3970.07 100.0 (3.75 μl) HKGS 9391.983 7094.569 1.32 1793.7 HKGS + 7790.2969117.004 0.85 1157.8 Erlotinib + DMSO HKGS + 10848.175 7696.983 1.411909.7 Erlotinib + LUT014 HKGS + 6291.861 8346.569 0.75 1021.4Cetuximab + DMSO HKGS + 11594.983 8095.397 1.43 1940.7 Cetuximab +LUT014

LUT014 increased phospho-ERK by 200-800% compared to the DMSO treatedcells. Erlotinib decreased phospho ERK compared to HKGS treated cells.LUT014 increased phospho-ERK when added to cells treated with Erlotinib.LUT014 increased phospho-ERK when added to cells treated with cetuximab.

Example 20 Permeation Studies Using a Topical Composition ComprisingLUT014

An ex vivo permeation and penetration experiment for a topicalcomposition comprising LUT-014 was conducted using MedFlux-HT™continuous flow through diffusion cells. A skin sample was placedbetween donor and receptor compartments of the diffusion cell. Thediffusion of the topical composition was measured using acitrate/phosphate buffer (pH 4.0) with 0.01% Brij as a receptorsolution. LUT014 permeated into the skin sample was extracted using90/10 acetonitrile/water as an extraction solvent.

The maximum accumulated level of LUT014 observed in the receptorsolution after 24 hours was less than 2 ng/mL.

Example 21

Toxicity studies for the present compounds using LUT014 as an exemplarycompound were conducted. The results are summarized below.

Oral administration of LUT014, for 7 days in the Wistar rat at doselevels of 250, 500 and 1000 mg/kg/day did not result in mortality.

Dermal administration of LUT014 was well tolerated in minipigs at levelsof 5 mg/kg/day for up to 6 days.

The results of in vitro Ames test showed that LUT014 is not mutagenic inthe Salmonella typhimurium reverse mutation assay and in the Escherichiacoli reverse mutation assay.

Since LUT014 induced an IVIS ≤3, no classification is required for eyeirritation or serious eye damage, as was observed by BCOP study.

LUT014 is classified as non-phototoxic (3T3 NRU)

TABLE 7 Toxicity Studies Study Results DRF oral in Oral administrationof Lut014, for 7 days in the Wistar Wistar Rats rat at dose levels of250, 500 and 1000 mg/kg/day did not result in mortality MTD DermalDermal administration of LUT014 was well tolerated in Minipigs minipigsat levels of 5 mg/kg/day for up to 6 days. Sensitization The testarticle is not a dermal sensitizer GP In vitro Lut014 is not mutagenicin the Salmonella typhimurium Ames test reverse mutation assay and inthe Escherichia coli reverse mutation assay. 20145601 - Lut014 inducedan IVIS ≤3, no classification is required BCOP for eye irritation orserious eye damage 3T3 NRU Lut014 is classified as non-phototoxic

Example 22

A Phase 1/2 multi-center two-phase study was devised.

Primary Objective:

To evaluate the safety, and pharmacokinetics of LUT014 in colorectalcancer patients who are receiving EGFR inhibitors.

Secondary Objectives:

Estimate the efficacy of LUT014 in the treatment of grade 1 and 2acneiform lesions occurring in colorectal cancer patients receiving EGFRinhibitors.

Patient Population:

Colorectal cancer patients receiving EGFR inhibitors who have developedacneiform lesions.

Methodology:

This is a multi-center, open-label, dose escalation study that willdetermine the maximum tolerated dose (MTD), establish thepharmacokinetics of LUT014, and estimate the efficacy of LUT014 intreating patients receiving EGFR inhibitor therapy and who havedeveloped acneiform lesions.

Enrollment will initially occur in cohorts of three subjects in aconventional 3+3 escalating dose design. Patients receiving EGFRinhibitors and who have developed grade 1 or 2 acneiform lesions will betreated with LUT014 for 4 weeks. The LUT014 gel will be applied eachmorning after bathing or showering. Application will be to the face and,the upper portion of the anterior and posterior chest. A thin layer ofthe gel will be applied.

In the initial cohort of LUT014 if no dose limiting toxicity (DLT)occurs in the initial 3 patients, or in 1 of 6 patients if this cohortgoes to 6 patients during the 4 weeks of therapy, the second cohort willbegin. For this second dosing regimen, patients will again have LUT014applied to their face, plus their upper anterior and posterior chest ona daily basis after bathing for 4 weeks. If no DLTs are observed in theinitial 3 patients treated in this cohort, or in 1 of 6 patients if thissecond cohort goes to 6 patients, a third cohort of 3 patients, or 6patients if this third cohort goes to 6 patients, will be treated. Thesepatients will also have LUT014 applied over their face, anterior andposterior chest on a daily basis after bathing for 4 weeks

For each dosing cohort, if no subject experiences a DLT, based onNational Cancer Institute (NCI) Common Terminology Criteria for AdverseEvents (CTCAE) v4.03, which constitutes a Grade 3 or higher toxicity,the subsequent group of three subjects will receive the next higherLUT014 dosing regimen. However, if one of the three initial subjectsexperiences a DLT, the cohort of subjects in that dosing regimen will beexpanded to six subjects. If at least two of the six subjects experiencea DLT, this will be considered a non-tolerated dose.

The MTD is defined as the highest dosing concentration of LUT014 atwhich fewer than two (of a cohort of up to six) subjects experience aDLT.

Determination of a DLT will require that the Grade 3 or greater toxicityoccur and be determined to be possibly, probably or definitely relatedto the study drug by an independent safety review committee.

Following completion of the dose escalation phase of the study, up to 60patients will be enrolled and randomized to have either LUT014 at theMTD or a smaller dose chosen by the sponsor or will be treated with anidentical appearing vehicle. The LUT014 or vehicle will be applied totheir skin over all areas with evidence of acneiform lesions. Patientswill be treated for 4 weeks.

1. A compound selected from (i) a compound of formula (I):

wherein R is selected from the group consisting of p-chlorophenyl,3-ethynylphenyl, 3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl,4-chloro-3-(trifluoromethyl)phenyl,3-(1,1-dimethylethyl)-1-methyl-TH-pyrazol-5-yl,3-(trifluoromethoxy)phenyl, 3,5-dihydroxyphenyl, phenyl-3-sulfonamide or3-(trifluoromethyl)phenyl, or a pharmaceutically acceptable salt or asolvate thereof; (ii) a compound of formula (II):

wherein R is NHR¹, wherein R¹ is 2-fluoro-4-iodophenyl, or apharmaceutically acceptable salt or a solvate thereof; (iii) a compoundof formula (III):

wherein R is NHR¹, wherein R¹ is 3-ethynylphenyl,3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl, or4-chloro-3-(trifluoromethyl) phenyl, or a pharmaceutically acceptablesalt or a solvate thereof, or a combination thereof.
 2. The compound offormula I of claim 1, wherein R is 3-(trifluoromethoxy)phenyl.
 3. Thecompound of formula I, II or III of claim 1, wherein the compoundinhibits the activity of BRaf.
 4. The compound of formula I, II or IIIof claim 1, wherein the compound increases the activity ofMitogen-Activated Protein Kinase (MAPK).
 5. The compound of formula I,II or III of claim 1, wherein the compound increases the activity ofMitogen-Activated Protein Kinase (MAPK) and wherein MAPK is anExtra-cellular Signal-Related Kinase (ERK).
 6. The compound of formulaI, II or III of claim 1, wherein the compound has a photo-irritationfactor (PIF) of less than
 5. 7. The compound of formula I, II or III ofclaim 1, wherein the compound has a mean photo effect (MPE) of less than0.15.
 8. A pharmaceutical composition, comprising a compound selectedfrom (i) a compound of formula (I):

wherein R is selected from the group consisting of p-chlorophenyl,3-ethynylphenyl, 3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl,4-chloro-3-(trifluoromethyl)phenyl,3-(1,1-dimethylethyl)-1-methyl-1H-pyrazol-5-yl,3-(trifluoromethoxy)phenyl, 3,5-dihydroxyphenyl, phenyl-3-sulfonamide or3-(trifluoromethyl)phenyl, or a pharmaceutically acceptable salt or asolvate thereof, (ii) a compound of formula (II):

wherein R is NHR¹, wherein R¹ is 2-fluoro-4-iodophenyl, or apharmaceutically acceptable salt or a solvate thereof; (iii) a compoundof formula (III):

wherein R is NHR1, wherein R1 is 3-ethynylphenyl,3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl, or4-chloro-3-(trifluoromethyl) phenyl, or a pharmaceutically acceptablesalt or a solvate thereof; or a combination thereof; and apharmaceutically acceptable carrier or excipient.
 9. The pharmaceuticalcomposition of claim 8, wherein the compound is the compound of formula(I), and wherein R is 3-(trifluoromethoxy)phenyl.
 10. The pharmaceuticalcomposition of claim 8, wherein the compound inhibits the activity ofBRaf and increases the activity of Mitogen-Activated Protein Kinase(MAPK).
 11. The pharmaceutical composition of claim 8, wherein thecompound inhibits the activity of BRaf and increases the activity ofMitogen-Activated Protein Kinase (MAPK), and wherein the MAPK is anExtra-cellular Signal-Related Kinase (ERK).
 12. The pharmaceuticalcomposition of claim 8, wherein the composition is formulated forsystemic administration.
 13. The pharmaceutical composition of claim 8,wherein the composition is formulated for topical administration. 14.The pharmaceutical composition of claim 8, wherein the composition isadministered orally in the form of a tablet, a capsule, a liquid, asuspension or a powder.
 15. The pharmaceutical composition of claim 8,wherein the composition is in the form of a gel, a hydrogel, anointment, a cream, a foam, a spray, a lotion, a liquid or a dermalpatch.
 16. The pharmaceutical composition of claim 8, wherein thecompound is present at a concentration of 1% w/w to 5% w/w of the totalweight of the composition.
 17. The pharmaceutical composition of claim8, wherein the compound is present at a concentration of 5% w/w to 10%w/w of the total weight of the composition.
 18. A method of treating,ameliorating, and/or preventing a cutaneous adverse reaction to EGFRinhibitors, PI3K inhibitors, MEK inhibitors or combinations thereof in asubject in need thereof, comprising administering a compositioncomprising a therapeutically effective amount of a compound selectedfrom (i) a compound of formula (I):

wherein R is selected from the group consisting of p-chlorophenyl,3-ethynylphenyl, 3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl,4-chloro-3-(trifluoromethyl)phenyl,3-(1,1-dimethylethyl)-1-methyl-TH-pyrazol-5-yl,3-(trifluoromethoxy)phenyl, 3,5-dihydroxyphenyl, phenyl-3-sulfonamide or3-(trifluoromethyl)phenyl, or a pharmaceutically acceptable salt or asolvate thereof; (ii) a compound of formula (II):

wherein R is NHR¹, wherein R¹ is 2-fluoro-4-iodophenyl, or apharmaceutically acceptable salt or a solvate thereof; (iii) a compoundof formula (III):

wherein R is NHR¹, wherein R¹ is 3-ethynylphenyl,3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl, or4-chloro-3-(trifluoromethyl) phenyl, or a pharmaceutically acceptablesalt or a solvate thereof; or a combination thereof, and apharmaceutically acceptable carrier or excipient.
 19. The method ofclaim 18, wherein the compound is the compound of formula (I), andwherein R is 3-(trifluoromethoxy)phenyl.
 20. The method of claim 18,wherein the cutaneous adverse reaction is selected from acneiform rash,papulopustular rash, abnormal scalp hair growth, abnormal facial hairgrowth, abnormal hair growth, abnormal eyelash growth, paronychia withor without pyogenic granulomas and telangiectasia and combinationsthereof.